U.S. patent number 7,067,512 [Application Number 10/292,876] was granted by the patent office on 2006-06-27 for substituted 1,4-benzodiazepines and uses thereof.
Invention is credited to Raul R Calvo, Theodore E Carver, Jr., Maxwell D Cummings, Bruce L Grasberger, Alexander J Kim, Louis V Lafrance, III, Tianbao Lu, Karen L Milkiewicz, Daniel J Parks.
United States Patent |
7,067,512 |
Lu , et al. |
June 27, 2006 |
Substituted 1,4-benzodiazepines and uses thereof
Abstract
The present invention is directed to novel 1,4-benzodiazepines,
pharmaceutical compositions thereof, and the use thereof as
inhibitors of HDM2-p53 interactions. Compounds have Formula I:
##STR00001## or a solvate, hydrate or pharmaceutically acceptable
salt thereof; wherein: X and Y are independently --C(O)--,
--CH.sub.2-- or --C(S)--; R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.7, R.sup.8, R.sup.b, R.sup.c, R.sup.d and M are defined
herein; R.sup.5 is hydrogen, alkyl, cycloalkyl, optionally
substituted aryl, optionally substituted heteroaryl, optionally
substituted aralkyl, optionally substituted heteroaralkyl,
carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aminocarbonyl,
aminocarbonylalkyl, alkylaminocarbonyl or alkylaminocarbonylalkyl;
R.sup.6 is cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, aralkyl,
heteroarylalkyl, or a saturated or partially unsaturated
heterocycle, each of which is optionally substituted; R.sup.9 is
cycloalkyl, aryl, heteroaryl, a saturated or partially unsaturated
heterocycle, cycloalkyl(alkyl), aralkyl or heteroarylalkyl, each of
which is optionally substituted; and R.sup.10 is
--(CH.sub.2).sub.n--CO.sub.2R.sup.b, --(CH.sub.2).sub.m--CO.sub.2M,
--(CH.sub.2).sub.i--OH or --(CH.sub.2).sub.j--CONR.sup.cR.sup.d n
is 0 8, m is 0 8, i is 1 8 and j is 0 8.
Inventors: |
Lu; Tianbao (Kennett Square,
PA), Lafrance, III; Louis V (West Chester, PA), Parks;
Daniel J (Exton, PA), Milkiewicz; Karen L (Exton,
PA), Calvo; Raul R (Royersford, PA), Cummings; Maxwell
D (Wayne, PA), Kim; Alexander J (Philadelphia, PA),
Grasberger; Bruce L (Trappe, PA), Carver, Jr.; Theodore
E (Downingtown, PA) |
Family
ID: |
23293137 |
Appl.
No.: |
10/292,876 |
Filed: |
November 13, 2002 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20030109518 A1 |
Jun 12, 2003 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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60331235 |
Nov 13, 2001 |
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Current U.S.
Class: |
514/221; 540/506;
540/505; 540/512; 540/504 |
Current CPC
Class: |
A61P
5/14 (20180101); C07D 409/04 (20130101); A61P
21/04 (20180101); A61P 1/04 (20180101); A61P
3/10 (20180101); A61P 25/00 (20180101); A61P
37/06 (20180101); C07D 403/10 (20130101); A61P
37/08 (20180101); C07D 405/04 (20130101); A61P
35/00 (20180101); C07D 401/04 (20130101); A61P
35/02 (20180101); A61P 13/12 (20180101); A61P
19/02 (20180101); A61P 21/00 (20180101); A61P
37/00 (20180101); C07D 243/14 (20130101); A61P
43/00 (20180101); A61P 17/04 (20180101); A61P
25/28 (20180101); A61P 5/00 (20180101); A61P
37/02 (20180101); A61P 7/06 (20180101); A61P
29/00 (20180101); A61P 17/00 (20180101) |
Current International
Class: |
C07D
243/12 (20060101); A61K 31/55 (20060101); C07D
243/18 (20060101); C07D 243/24 (20060101) |
Field of
Search: |
;540/504,505,506,512
;514/221 |
References Cited
[Referenced By]
U.S. Patent Documents
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5250679 |
October 1993 |
Blackburn et al. |
5272158 |
December 1993 |
Hartman et al. |
5389631 |
February 1995 |
Claremon et al. |
5441952 |
August 1995 |
Claremon et al. |
5795887 |
August 1998 |
Aquino et al. |
5817751 |
October 1998 |
Szardenings et al. |
5990145 |
November 1999 |
Wehner et al. |
6492553 |
December 2002 |
Hulme et al. |
6600016 |
July 2003 |
Campian et al. |
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Foreign Patent Documents
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WO 99/38844 |
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Aug 1999 |
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WO |
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WO |
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WO |
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WO 01/04103 |
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Jan 2001 |
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WO |
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WO 01/10799 |
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Feb 2001 |
|
WO |
|
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|
Primary Examiner: Kifle; Bruck
Attorney, Agent or Firm: Donnelly; Laura
Parent Case Text
This application claims priority under 35 U.S.C. .sctn. 119(e) to
U.S. Provisional Application No. 60/331,235, filed Nov. 13, 2001,
which is fully incorporated by reference herein.
Claims
What is claimed is:
1. A compound of Formula I: ##STR00005## or pharmaceutically
acceptable salt thereof; wherein: X and Y are independently
--C(O)--, --CH.sub.2-- or --C(S)--; R.sup.1, R.sup.3, and R.sup.4
are independently hydrogen, halo, alkyl, alkenyl, alkynyl,
cycloalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted heteroaryl, optionally substituted
heteroaralkyl, alkoxy, optionally substituted aryloxy, optionally
substituted heteroaryloxy, cyano, amino, alkanoylamino, nitro,
hydroxy, carboxy, or alkoxycarbonyl; or R.sup.3 and R.sup.4 are
taken together to form --(CH.sub.2).sub.u--, where u is 3 6,
--CH.dbd.CH--CH.dbd.CH-- or --CH.sub.2CH.dbd.CHCH.sub.2--; R.sup.2
is hydrogen, halo, C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, acetylamino, C.sub.1-6 alkoxy, phenyl,
halophenyl, hydroxyphenyl, C.sub.1-6 alkoxyphenyl, C.sub.1-6
alkylphenyl, aminophenyl, C.sub.1-6 alkylenedioxyphenyl,
hydroxycarbonylphenyl, thienyl, C.sub.1-6 alkylthienyl, furanyl,
pyrrolyl, amino, C.sub.1-6 hydroxyalkyl or cyano; R.sup.5 is
hydrogen, alkyl, cycloalkyl, optionally substituted aryl,
optionally substituted heteroaryl, optionally substituted aralkyl,
optionally substituted heteroaralkyl, carboxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl,
alkylaminocarbonyl or alkylaminocarbonylalkyl; R.sup.6 is
cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, or
a saturated or partially unsaturated heterocycle, each of which is
optionally substituted; R.sup.7 and R.sup.8 are independently
hydrogen or alkyl; R.sup.9 is cycloalkyl, aryl, heteroaryl, a
saturated or partially unsaturated heterocycle, cycloalkyl(alkyl),
aralkyl or heteroarylalkyl, each of which is optionally
substituted; and R.sup.10 is --(CH.sub.2).sub.n--CO.sub.2R.sup.b,
--(CH.sub.2).sub.m--CO.sub.2M, --(CH.sub.2).sub.i--OH or
--(CH.sub.2).sub.j--CONR.sup.cR.sup.d where R.sup.b is hydrogen,
alkyl, optionally substituted cycloalkyl, or optionally
substituted, saturated or partially unsaturated heterocycle; M is a
cation; R.sup.c and R.sup.d are independently hydrogen, alkyl,
hydroxyalkyl, carboxyalkyl, aminoalkyl, optionally substituted
cycloalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, and an optionally substituted, saturated or
partially unsaturated heterocycle; and n is 0 8, m is 0 8, i is 1 8
and j is 0 8.
2. A compound of Formula I: ##STR00006## or pharmaceutically
acceptable salt thereof; wherein: X and Y are independently
--C(O)--, --CH.sub.2-- or --C(S)--; R.sup.1, R.sup.3, and R.sup.4
are independently hydrogen, halo, alkyl, alkenyl, alkynyl,
cycloalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted heteroaryl, optionally substituted
heteroaralkyl, alkoxy, optionally substituted aryloxy, optionally
substituted heteroaryloxy, cyano, amino, alkanoylamino, nitro,
hydroxy, carboxy, or alkoxycarbonyl; or R.sup.3 and R.sup.4 are
taken together to form --(CH.sub.2).sub.u--, where u is 3 6,
--CH.dbd.CH--CH.dbd.CH-- or --CH.sub.2CH.dbd.CHCH.sub.2--; R.sup.2
is iodo, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl,
t-butyl, sec-butyl, cyclopropyl, ethynyl, acetylamino, methoxy,
3-chlorophenyl, 4-chlorophenyl, 4-hydroxyphenyl, 3-methoxyphenyl,
4-methylphenyl, 3-methylphenyl, 3-isopropylphenyl, 3-aminophenyl,
3,4-methylenedioxyphenyl, 4-hydroxycarbonylphenyl thien-3-yl,
4-methylthien-2-yl, furan-2-yl, 1H-pyrrol-3-yl, amino,
2-hydroxyethyl, hydroxymethyl, furan-3-yl, or vinyl; R.sup.5 is
hydrogen, alkyl, cycloalkyl, optionally substituted aryl,
optionally substituted heteroaryl, optionally substituted aralkyl,
optionally substituted heteroaralkyl, carboxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl,
alkylaminocarbonyl or alkylaminocarbonylalkyl; R.sup.6 is
cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, or
a saturated or partially unsaturated heterocycle, each of which is
optionally substituted; R.sup.7 and R.sup.8 are independently
hydrogen or alkyl; R.sup.9 is cycloalkyl, aryl, heteroaryl, a
saturated or partially unsaturated heterocycle, cycloalkyl(alkyl),
aralkyl or heteroarylalkyl, each of which is optionally
substituted; and R.sup.10 is --(CH.sub.2).sub.n--CO.sub.2R.sup.b,
--(CH.sub.2).sub.m--CO.sub.2M, --(CH.sub.2).sub.i--OH or
--(CH.sub.2).sub.j--CONR.sup.cR.sup.d where R.sup.b is hydrogen,
alkyl, optionally substituted cycloalkyl, or optionally
substituted, saturated or partially unsaturated heterocycle; M is a
cation; R.sup.c and R.sup.d are independently hydrogen, alkyl,
hydroxyalkyl, carboxyalkyl, aminoalkyl, optionally substituted
cycloalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, and an optionally substituted, saturated or
partially unsaturated heterocycle; and n is 0 8, m is 0 8, i is 1 8
and j is 0 8.
3. The compound of claim 1, wherein R.sup.2 is halo or phenyl.
4. The compound of claim 3, wherein R.sup.2 is iodo.
5. A compound of Formula I: ##STR00007## or pharmaceutically
acceptable salt thereof; wherein: X and Y are independently
--C(O)--, --CH.sub.2-- or --C(S)--; R.sup.1, R.sup.2, and R.sup.4
are independently hydrogen, halo, alkyl, alkenyl, alkynyl,
cycloalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted heteroaryl, optionally substituted
heteroaralkyl, alkoxy, optionally substituted aryloxy, optionally
substituted heteroaryloxy, cyano, amino, alkanoylamino, nitro,
hydroxy, carboxy, or alkoxycarbonyl; or R.sup.1 and R.sup.2 are
taken together to form --(CH.sub.2).sub.u--, where u is 3 6,
--CH.dbd.CH--CH.dbd.CH-- or --CH.sub.2CH.dbd.CHCH.sub.2--; R.sup.3
is hydrogen, alkyl, phenyl, fluoro, chloro, iodo or methyl; R.sup.5
is hydrogen, alkyl, cycloalkyl, optionally substituted aryl,
optionally substituted heteroaryl, optionally substituted aralkyl,
optionally substituted heteroaralkyl, carboxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl,
alkylaminocarbonyl or alkylaminocarbonylalkyl; R.sup.6 is
cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, or
a saturated or partially unsaturated heterocycle, each of which is
optionally substituted; R.sup.7 and R.sup.8 are independently
hydrogen or alkyl; R.sup.9 is cycloalkyl, aryl, heteroaryl, a
saturated or partially unsaturated heterocycle, cycloalkyl(alkyl),
aralkyl or heteroarylalkyl, each of which is optionally
substituted; and R.sup.10 is --(CH.sub.2).sub.n--CO.sub.2R.sup.b,
--(CH.sub.2).sub.m--CO.sub.2M, --(CH.sub.2).sub.i--OH or
--(CH.sub.2).sub.j--CONR.sup.cR.sup.d where R.sup.b is hydrogen,
alkyl, optionally substituted cycloalkyl, or optionally
substituted, saturated or partially unsaturated heterocycle; M is a
cation; R.sup.c and R.sup.d are independently hydrogen, alkyl,
hydroxyalkyl, carboxyalkyl, aminoalkyl, optionally substituted
cycloalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, and an optionally substituted, saturated or
partially unsaturated heterocycle; and n is 0 8, m is 0 8, i is 1 8
and j is 0 8.
6. The compound of claim 5, wherein R.sup.3 is hydrogen.
7. A compound of Formula I: ##STR00008## or pharmaceutically
acceptable salt thereof; wherein: X and Y are independently
--C(O)--, --CH.sub.2-- or --C(S)--; R.sup.1, R.sup.2, R.sup.3, and
R.sup.4 are independently hydrogen, halo, alkyl, alkenyl, alkynyl,
cycloalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted heteroaryl, optionally substituted
heteroaralkyl, alkoxy, optionally substituted aryloxy, optionally
substituted heteroaryloxy, cyano, amino, alkanoylamino, nitro,
hydroxy, carboxy, or alkoxycarbonyl; or R.sup.1 and R.sup.2, or
R.sup.2 and R.sup.3,-or R.sup.3 and R.sup.4 are taken together to
form --(CH.sub.2).sub.u--, where u is 3 6, --CH.dbd.CH--CH.dbd.CH--
or --CH.sub.2CH.dbd.CHCH.sub.2--; R.sup.5 is hydrogen, alkyl,
cycloalkyl, optionally substituted aryl, optionally substituted
heteroaryl, optionally substituted aralkyl, optionally substituted
heteroaralkyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,
aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl or
alkylaminocarbonylalkyl; R.sup.6 is trifluoromethylphenyl,
halophenyl, C.sub.1-6 alkoxyphenyl, halo(C.sub.1-4)alkoxyphenyl,
naphthyl, benzyloxyphenyl, phenoxyphenyl, dihydrobenzodioxinyl,
trifluoromethyl-halophenyl, pyridyl, thienyl, C.sub.1-6
alkylthienyl, halothienyl, bithienyl, C.sub.1-6 alkylbenzothienyl,
(halophenyl)furanyl, quinolinyl, biphenyl, indolyl,
(trifluoromethylsulfanyl)phenyl, (trifluoromethylphenyl)furanyl,
halo(C.sub.1-4)alkoxyphenyl, benzofuranyl, cyanophenyl,
halopyridyl, (methylsulfanyl)phenyl, pyrrolidinylphenyl, C.sub.2-6
alkenyl(C.sub.3-7)cycloalkenyl, cubanyl or halocubanyl; R.sup.7 and
R.sup.8 are independently hydrogen or alkyl; R.sup.9 is cycloalkyl,
aryl, heteroaryl, a saturated or partially unsaturated heterocycle,
cycloalkyl(alkyl), aralkyl or heteroarylalkyl, each of which is
optionally substituted; and R.sup.10 is
--(CH.sub.2).sub.n--CO.sub.2R.sup.b, --(CH.sub.2).sub.m--CO.sub.2M,
--(CH.sub.2).sub.i--OH or --(CH.sub.2).sub.j--CONR.sup.cR.sup.d
where R.sup.b is hydrogen, alkyl, optionally substituted
cycloalkyl, or optionally substituted, saturated or partially
unsaturated heterocycle; M is a cation; R.sup.c and R.sup.d are
independently hydrogen, alkyl, hydroxyalkyl, carboxyalkyl,
aminoalkyl, optionally substituted cycloalkyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl, and
an optionally substituted, saturated or partially unsaturated
heterocycle; and n is 0 8, m is 0 8, i is 1 8 and j is 0 8.
8. A compound of Formula I: ##STR00009## or pharmaceutically
acceptable salt thereof; wherein: X and Y are independently
--C(O)--, --CH.sub.2-- or --C(S)--; R.sup.1, R.sup.2, R.sup.3, and
R.sup.4 are independently hydrogen, halo, alkyl, alkenyl, alkynyl,
cycloalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted heteroaryl, optionally substituted
heteroaralkyl, alkoxy, optionally substituted aryloxy, optionally
substituted heteroaryloxy, cyano, amino, alkanoylamino, nitro,
hydroxy, carboxy, or alkoxycarbonyl; or R.sup.1 and R.sup.2, or
R.sup.2 and R.sup.3, -or R.sup.3 and R.sup.4 are taken together to
form --(CH.sub.2).sub.u--, where u is 3 6, --CH.dbd.CH--CH.dbd.CH--
or --CH.sub.2CH.dbd.CHCH.sub.2--; R.sup.5 is hydrogen, alkyl,
cycloalkyl, optionally substituted aryl, optionally substituted
heteroaryl, optionally substituted aralkyl, optionally substituted
heteroaralkyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,
aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl or
alkylaminocarbonylalkyl; R.sup.6 is 2-trifluoromethylphenyl,
3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-chlorophenyl,
3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl,
4-bromophenyl, 4-iodophenyl, 4-methylphenyl, 4-ethylphenyl,
4-trifluoromethoxyphenyl, 4-isopropylphenyl, phenyl,
4-methoxy-phenyl, naphthalen-2-yl, 4-tert-butylphenyl,
4-benzyloxyphenyl, 4-phenoxyphenyl, 3,4-dichlorophenyl,
3,4-dimethoxyphenyl, 2,3-dihydrobenzo[1,4]dioxin-6-yl,
4-bromo-2-fluorophenyl, 2-fluoro-4-trifluoromethylphenyl,
3-fluoro-4-trifluoromethylphenyl, 4-chloro-3-trifluoromethylphenyl,
4-chloro-3-fluorophenyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl,
thien-3-yl, 5-methylthien-2-yl, 3-methylthien-2-yl,
4-bromothien-2-yl, 5-[2,2']bithienyl,
3-methylbenzo[b]thiophen-2-yl, 5-(2-chlorophenyl)-furan-2-yl,
5-(3-chlorophenyl)-furan-2-yl, quinolin-3-yl, biphen-4-yl,
indol-2-yl, indol-3-yl, 4-trifluoromethylsulfanylphenyl,
5-(3-trifluoromethylphenyl)furan-2-yl,
4-(1,1,2,2-tetrafluoroethoxy)phenyl, 4-difluoromethoxyphenyl,
benzofuran-2-yl, 4-cyanophenyl, 6-chloropyrid-3-yl,
4-methylsulfanylphenyl, 4-pyrrolidin-1-ylphenyl,
5-chlorothien-2-yl, 4-isopropenylcyclohex-1-enyl or
1-chlorocuban-4-yl; R.sup.7 and R.sup.8 are independently hydrogen
or alkyl; R.sup.9 is cycloalkyl, aryl, heteroaryl, a saturated or
partially unsaturated heterocycle, cycloalkyl(alkyl), aralkyl or
heteroarylalkyl, each of which is optionally substituted; and
R.sup.10 is --(CH.sub.2).sub.n--CO.sub.2R.sup.b,
--(CH.sub.2).sub.m--CO.sub.2M, --(CH.sub.2).sub.i--OH or
--(CH.sub.2).sub.j--CONR.sup.cR.sup.d where R.sup.b is hydrogen,
alkyl, optionally substituted cycloalkyl, or optionally
substituted, saturated or partially unsaturated heterocycle; M is a
cation; R.sup.c and R.sup.d are independently hydrogen, alkyl,
hydroxyalkyl, carboxyalkyl, aminoalkyl, optionally substituted
cycloalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, and an optionally substituted, saturated or
partially unsaturated heterocycle; and n is 0 8, m is 0 8, i is 1 8
and j is 0 8.
9. The compound of claim 8, wherein R.sup.6 is 4-chlorophenyl,
4-bromophenyl, 4-trifluoromethylphenyl or
4-trifluoromethoxyphenyl.
10. The compound of claim 7, wherein R.sup.6 is 4-chlorophenyl.
11. A compound of Formula I: ##STR00010## or pharmaceutically
acceptable salt thereof; wherein: X and Y are independently
--C(O)--, --CH.sub.2-- or --C(S)--; R.sup.1, R.sup.2, R.sup.3, and
R.sup.4 are independently hydrogen, halo, alkyl, alkenyl, alkynyl,
cycloalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted heteroaryl, optionally substituted
heteroaralkyl, alkoxy, optionally substituted aryloxy, optionally
substituted heteroaryloxy, cyano, amino, alkanoylamino, nitro,
hydroxy, carboxy, or alkoxycarbonyl; or R.sup.1 and R.sup.2, or
R.sup.2 and R.sup.3, or R.sup.3 and R.sup.4 are taken together to
form --(CH.sub.2).sub.u--, where u is 3 6, --CH.dbd.CH--CH.dbd.CH--
or --CH.sub.2CH.dbd.CHCH.sub.2--; R.sup.5 is hydrogen, alkyl,
cycloalkyl, optionally substituted aryl, optionally substituted
heteroaryl, optionally substituted aralkyl, optionally substituted
heteroaralkyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,
aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl or
alkylaminocarbonylalkyl; R.sup.6 is cycloalkyl, aryl, hetroaryl,
cycloalkylalkyl, hetroarylalkyl, or a saturated or partially
unsaturated hetrocycle, each of which is optionally substituted;
R.sup.9 is cycloalkyl, aryl, heteroaryl, a saturated or partially
unsaturated heterocycle, cycloalkyl(alkyl), aralkyl or
heteroarylalkyl, each of which is optionally substituted; and
R.sup.10 is --(CH.sub.2).sub.n--CO.sub.2R.sup.b,
--(CH.sub.2).sub.m--CO.sub.2M, --(CH.sub.2).sub.i--OH or
--(CH.sub.2).sub.j--CONR.sup.cR.sup.d where R.sup.b is hydrogen,
alkyl, optionally substituted cycloalkyl, or optionally
substituted, saturated or partially unsaturated heterocycle; M is a
cation; R.sup.c and R.sup.d are independently hydrogen, alkyl,
hydroxyalkyl, carboxyalkyl, aminoalkyl, optionally substituted
cycloalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, and an optionally substituted, saturated or
partially unsaturated heterocycle; and n is 0 8, m is 0 8, i is 1 8
and j is 0 8.
12. The compound of claim 11, wherein R.sup.7 and R.sup.8 are
hydrogen.
13. A compound of Formula I: ##STR00011## or pharmaceutically
acceptable salt thereof; wherein: X and Y are independently
--C(O)--, --CH.sub.2-- or --C(S)--; R.sup.1, R.sup.2, R.sup.3, and
R.sup.4 are independently hydrogen, halo, alkyl, alkenyl, alkynyl,
cycloalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted heteroaryl, optionally substituted
heteroaralkyl, alkoxy, optionally substituted aryloxy, optionally
substituted heteroaryloxy, cyano, amino, alkanoylamino, nitro,
hydroxy, carboxy, or alkoxycarbonyl; or R.sup.1 and R.sup.2, or
R.sup.2 and R.sup.3, -or R.sup.3 and R.sup.4 are taken together to
form --(CH.sub.2).sub.u--, where u is 3 6, --CH.dbd.CH--CH.dbd.CH--
or --CH.sub.2CH.dbd.CHCH.sub.2--; R.sup.5 is hydrogen, alkyl,
cycloalkyl, optionally substituted aryl, optionally substituted
heteroaryl, optionally substituted aralkyl, optionally substituted
heteroaralkyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,
aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl or
alkylaminocarbonylalkyl; R.sup.6 is cycloalkyl, aryl, hetroaryl,
cycloalkylalkyl, hetroarylalkyl, or a saturated or partially
unsaturated hetrocycle, each of which is optionally substituted;
R.sup.7 and R.sup.8 are independently hydrogen or alkyl; wherein
R.sup.9 is optionally substituted C.sub.6-10 aryl or optionally
substituted C.sub.6-10 ar(C.sub.1-6)alkyl; R.sup.10 is
--(CH.sub.2).sub.n--CO.sub.2R.sup.b, --(CH.sub.2).sub.m--CO.sub.2M,
--(CH.sub.2).sub.i--OH or --(CH.sub.2).sub.j--CONR.sup.cR.sup.d
where R.sup.b is hydrogen, alkyl, optionally substituted
cycloalkyl, or optionally substituted, saturated or partially
unsaturated heterocycle; M is a cation; R.sup.c and R.sup.d are
independently hydrogen, alkyl, hydroxyalkyl, carboxyalkyl,
aminoalkyl, optionally substituted cycloalkyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl, and
an optionally substituted, saturated or partially unsaturated
heterocycle; and n is 0 8, m is 0 8, i is 1 8 and j is 0 8.
14. The compound of claim 13, wherein R.sup.9 is phenyl,
4-chlorophenyl, 4-chlorobenzyl, benzyl, cyclohexyl,
cyclohexylmethyl, 4-hydroxyphenyl, pyridylmethyl, 4-fluorophenyl,
4-trifluoromethylphenyl, 4-iodobenzyl, 4-bromobenzyl, thien-2-yl,
thien-2-ylmethyl, naphth-2-ylmethyl, pyrid-2-ylethyl,
3-methylphenyl, 4-methylphenyl, 4-ethylphenyl,
4-chloro-3-fluorophenyl, 2-fluoro-4-trifluoromethylphenyl,
4-hydroxycarbonylphenyl, naphthalen-2-yl, naphthalen-1-yl,
4-iodophenyl, 4-bromophenyl, 3,4-dichlorophenyl, 2-chlorophenyl,
4-tert-butylphenyl, 4-isopropylphenyl, 3-chlorophenyl,
4-trifluoromethoxyphenyl, 3-hydroxyphenyl, 4-hydroxybenzyl,
4-trifluoromethylbenzyl, naphth-1-ylmethyl, 6-chloropyrid-3-yl, or
6-methylpyrid-3-yl.
15. The compound of claim 13, wherein R.sup.9 is halophenyl or
halobenzyl.
16. The compound of claim 13, wherein R.sup.9 is phenyl or
4-chlorophenyl.
17. A compound of Formula I: ##STR00012## or pharmaceutically
acceptable salt thereof; wherein: X and Y are independently
--C(O)--, --CH.sub.2-- or --C(S)--; R.sup.1, R.sup.2, R.sup.3, and
R.sup.4 are independently hydrogen, halo, alkyl, alkenyl, alkynyl,
cycloalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted heteroaryl, optionally substituted
heteroaralkyl, alkoxy, optionally substituted aryloxy, optionally
substituted heteroaryloxy, cyano, amino, alkanoylamino, nitro,
hydroxy, carboxy, or alkoxycarbonyl; or R.sup.1 and R.sup.2, or
R.sup.2 and R.sup.3, or R.sup.3 and R.sup.4 are taken together to
form --(CH.sub.2).sub.u--, where u is 3 6, --CH.dbd.CH--CH.dbd.CH--
or --CH.sub.2CH.dbd.CHCH.sub.2--; R.sup.5 is hydrogen, alkyl,
cycloalkyl, optionally substituted aryl, optionally substituted
heteroaryl, optionally substituted aralkyl, optionally substituted
heteroaralkyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,
aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl or
alkylaminocarbonylalkyl; R.sup.6 is cycloalkyl, aryl, hetroaryl,
cycloalkylalkyl, hetroarylalkyl, or a saturated or partially
unsaturated hetrocycle, each of which is optionally substituted;
R.sup.7 and R.sup.8 are independently hydrogen or alkyl; R.sup.9 is
cycloalkyl, aryl, heteroaryl, a saturated or partially unsaturated
heterocycle, cycloalkyl(alkyl), aralkyl or heteroarylalkyl, each of
which is optionally substituted; and R.sup.10 is --COOR.sup.b or
--CH.sub.2--COOR.sup.b, where R.sup.b is hydrogen or C.sub.1-6
alkyl; or R.sup.10 is --COOM, or --CH.sub.2--COOM, where M is
Na.sup.+ or K.sup.+.
18. The compound of claim 17, wherein R.sup.10 is --COOR.sup.b or
--CH.sub.2--COOR.sup.b, where R.sup.b is hydrogen, methyl, ethyl,
propyl or tert-butyl.
19. The compound of claim 17, wherein R.sup.10 is --COOH or --COOM,
where M is Na.sup.+ or K.sup.+.
20. The compound of claim 1, wherein R.sup.10 is --CH.sub.2OH or
--CH.sub.2CH.sub.2OH, or --CH.sub.2--CONR.sub.cR.sup.d or
--CONR.sup.cR.sup.d, where R.sup.c and R.sup.d are independently
hydrogen, methyl, ethyl, propyl, t-butyl, hydroxymethyl,
hydroxyethyl, hydroxypropyl, aminomethyl, aminoethyl, aminopropyl,
carboxymethyl, carboxyethyl, carboxypropyl, cyclopentyl,
cyclohexyl, phenyl or benzyl.
21. The compound of claim 1, wherein R.sup.10 is
--CH.sub.2--CONR.sup.cR.sup.d or --CONR.sup.cR.sup.d, where R.sup.c
and R.sup.d are independently hydrogen, methyl, hydroxyethyl,
3-carboxypropyl, 1-carboxy-2-methylpropyl, hydroxy, 4-carboxybutyl,
5-carboxypentyl, 2-(methoxycarbonyl)ethyl or
2-(hydroxyguanidino)ethyl.
22. The compound of claim 1, wherein said compound is selected from
the group consisting of:
(4-chloro-phenyl)-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydr-
o-benzo[e][1,4]diazepin-4-yl]-acetic acid;
2-[7-bromo-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]-
diazepin-4-yl]-3-(4-chloro-phenyl)-propionic acid;
2-(4-chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetra-
hydro-benzo[e][1,4]diazepin-4-yl]-acetamide;
[7-chloro-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]d-
iazepin-4-yl]-(4-chloro-phenyl)-acetic acid;
(4-chloro-phenyl)-[3-(4-chloro-phenyl)-7-ethynyl-2,5-dioxo-1,2,3,5-tetrah-
ydro-benzo[e][1,4]diazepin-4-yl]-acetic acid;
[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]dia-
zepin-4-yl]-p-tolyl-acetic acid;
(4-chloro-3-fluoro-phenyl)-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5--
tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid;
(4-chloro-phenyl)-[3-(4-chloro-phenyl)-7-ethyl-2,5-dioxo-1,2,3,5-tetrahyd-
ro-benzo[e][1,4]diazepin-4-yl]-acetic acid;
(4-chloro-phenyl)-[3-(4-chloro-phenyl)-7-isopropyl-2,5-dioxo-1,2,3,5-tetr-
ahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid;
(4-bromo-phenyl)-[3-(4-chloro-phenyl)-7-isopropyl-2,5-dioxo-1,2,3,5-tetra-
hydro-benzo[e][1,4]diazepin-4-yl]-acetic acid;
[3-(4-chloro-3-fluoro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e-
][1,4]diazepin-4-yl]-(4-chloro-phenyl)-acetic acid;
[3-(4-chlorophenyl)-7-phenyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]di-
azepin-4-yl]-phenylacetic acid;
[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]dia-
zepin-4-yl]-(4-fluoro-phenyl)-acetic acid;
[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]dia-
zepin-4-yl]-(4-trifluoromethyl-phenyl)-acetic acid;
(4-chloro-phenyl)-[7-iodo-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-
-tetrahydrobenzo[e][1,4]diazepin-4-yl]-acetic acid;
(4-chloro-phenyl)-[7-iodo-2,5-dioxo-3-(4-trifluoromethyl-phenyl)-1,2,3,5--
tetrahydrobenzo[e][1,4]diazepin-4-yl]-acetic acid;
[3-(4-bromo-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diaz-
epin-4-yl]-(4-chloro-phenyl)-acetic acid;
[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]dia-
zepin-4-yl]-(4-isopropyl-phenyl)-acetic acid;
(4-chloro-phenyl)-[3-(4-chloro-phenyl)-7-cyano-2,5-dioxo-1,2,3,5-tetrahyd-
ro-benzo[e][1,4]diazepin-4-yl]-acetic acid;
3-(4-chloro-phenyl)-4-(3-hydroxy-1-phenyl-propyl)-7-iodo-3,4-dihydro-1H-b-
enzo[e][1,4]diazepine-2,5-dione;
2-(4-chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetra-
hydro-benzo[e][1,4]diazepin-4-yl]-N-hydroxy-acetamide;
[7-bromo-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]di-
azepin-4-yl]-(4-chloro-phenyl)-acetic acid;
[8-chloro-3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e-
][1,4]diazepin-4-yl]-(4-chloro-phenyl)-acetic acid;
5-{2-(4-chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-te-
trahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-pentanoic acid;
3-{2-(4-chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-te-
trahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-propionic acid;
5-[4-[carboxy-(4-chloro-phenyl)-methyl]-3-(4-chloro-phenyl)-7-iodo-2,5-di-
oxo-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-yl]-pentanoic acid;
and pharmaceutically-acceptable salts thereof.
23. The compound of claim 1, wherein said compound is selected from
the group consisting of:
(4-chlorophenyl)-[3-(4-chlorophenyl)-7-iodo-5-oxo-1,2,3,5-tetrahydro-benz-
o[e][1,4]diazepin-4-yl]acetic acid;
3-(4-chloro-phenyl)-3-[3-(4-chloro-phenyl)-7-iodo-5-oxo-1,2,3,5-tetrahydr-
o-benzo[e][1,4]diazepin-4-yl]-propionic acid;
(4-chloro-phenyl)-[3-(4-chloro-phenyl)-7-iodo-5-oxo-2-thioxo-1,2,3,5-tetr-
ahydro-benzo[e][1,4]diaze pin-4-yl]-acetic acid;
3-(4-chloro-phenyl)-4-[1-(4-chloro-phenyl)-2-hydroxy-ethyl]-7-iodo-1,3,4,-
5-tetrahydro-benzo[e][1,4]diazepin-2-one;
3-(4-chloro-phenyl)-4-[1-(4-chloro-phenyl)-2-hydroxy-ethyl]-7-iodo-1,2,3,-
4-tetrahydro-benzo[e][1,4]diazepin-5-one; and
pharmaceutically-acceptable salts thereof.
24. A compound according to claims 1, in the form of a
hydrochloride, acetate, trifluoroacetate or fumarate salt.
25. A pharmaceutical composition, comprising: (a) a compound of 1,
or a salt, hydrate or prodrug thereof; and (b) one or more
pharmaceutically-acceptable excipients.
26. The composition of claim 25, wherein the composition is
sterile.
27. The composition of claim 25, further comprising: (c) at least
one additional substance selected from the group consisting of
synergists, stabilizing substances, antineoplastic agents,
anticancer agents, and cytostatic agents.
28. The composition of claim 25, wherein said compound is present
in an amount between about 0.5 and about 100 milligrams.
29. The composition of claim 25, suitable for administration by a
subcutaneous, intravenous, intramuscular, intraperitoneal, buccal,
or ocular route, rectally, parenterally, instrasystemically,
intravaginally, topically, orally, or as an oral or nasal
spray.
30. The composition of claim 25, suitable for parenteral
administration, wherein said compound is present in an amount
between about 0.5 and about 100 milligrams.
31. The composition of claim 25, suitable for parenteral
administration, wherein said compound is present in an amount
between about 0.5 and about 10 milligrams.
32. The composition of claim 25, suitable for oral administration,
wherein said compound is present in an amount between about 0.5 and
about 100 milligrams.
33. The composition of claim 25, suitable for oral administration,
wherein said compound is present in an amount between about 25 and
about 100 milligrams.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is in the area of novel 1,4-benzodiazepines
and salts thereof, their syntheses, and their use as inhibitors of
MDM2 and HDM2 oncoproteins.
2. Related Art
This invention relates to compounds that bind to the human protein
HDM2 and interfere with its interaction with other proteins,
especially the tumor suppressor protein p53. HDM2 is the expression
product of hdm2, an oncogene that is overexpressed in a variety of
cancers, especially soft tissue sarcomas (Momand, J., et al., Nucl.
Acids Res. 26:3453 3459 (1998)).
p53 is a transcription factor that plays a pivotal role in the
regulation of the balance between cell proliferation and cell
growth arrest/apoptosis. Under normal conditions, the half-life of
p53 is very short, and consequently the level of p53 in cells is
low. However, in response to cellular DNA damage, cellular stress,
or other factors, levels of p53 increase. This increase in p53
levels in turn increases the transcription of a number of genes
which induces the cell to either arrest growth or undergo apoptosis
(i.e., controlled cell death). The function of p53 is to prevent
the uncontrolled proliferation of cells and thus protect the
organism from the development of cancer (for a review, see Levine,
A. J., Cell 88:323 331 (1997)).
p53 is a latent and short-lived transcription factor which is
induced by, and is an integration point for, a range of cellular
stresses including DNA damage, UV damage, spindle damage, hypoxia,
inflammatory cytokines, viral infection, activated oncogenes, and
ribonucleotide depletion. Activation of p53 mediates a change in
the balance of gene expression such that expression of many genes
involved in proliferation is repressed while a range of genes
involved in growth arrest (such as p21WAF1 and GADD45), repair
(such as p53RE) and apoptosis (such as Bax, Killer/DR5 and PIGs) is
activated. The biological outcome of p53 activation (whether
permanent or transient growth arrest or apoptosis) is dependent on
several factors including the type and strength of the inducing
stress, and the type of cell or tissue.
p53 and MDM2 exist in a negative regulatory feedback loop in which
p53 stimulates transcription of the mdm2 gene while MDM2 binds to
p53 and targets it for degradation by the 26S proteosome. The key
element in the p53induction process is disruption of the p53-MDM2
complex which permits p53 to accumulate in the nucleus. This
mechanism appears to be common to all of the pathways by which p53
becomes activated, although recent evidence has indicated that
there is considerable variation in the molecular events by which
this is actually achieved.
Inactivation of the p53 tumor suppressor is a frequent event in
human neoplasia. The inactivation can occur by mutation of the p53
gene or through binding to viral or cellular oncogene proteins,
such as the SV40 large T antigen and MDM2. While the mechanism
through which wild-type p53 suppresses tumor cell growth is as yet
poorly defined, it is clear that one key feature of the growth
suppression is the property of p53 to act as a transcription factor
(Farmer, G., et al., Nature 358: 83 86 (1992); Funk, W. D. et al.,
Mol. Cell. Biol. 12: 2866 2871 (1992); Kern, S. E., et al., Science
256:827 830 (1992)). Currently, considerable effort is being made
to identify growth control genes that are regulated by p53 binding
to sequence elements near or within these genes. A number of such
genes have been identified. In cases such as the muscle creatine
kinase gene (Weintraub, H., et al., Proc. Natl. Acad. Sci. U.S.A.,
88:4570 4571 (1991); Zambetti, G. P., et al., Genes Dev. 6:1143
1152 (1992)) and a GLN retroviral element (Zauberman, A., et al.,
EMBO J. 12:2799 2808 (1993)), the role these genes might play in
the suppression of growth control is unclear. Yet there are other
examples, namely mdm2 (Barak, Y., et al. EMBO J. 12:461 468 (1993);
Wu, X., et al., Genes Dev. 7:1126 1132(1993)) GADD 45 (Kastan, M.
B., et al., Cell 71:587 597(1992)) and WAF1 or CIP1 (El-Beiry, W.
S., et al., Cell 75:817 825 (1993); Harper, J. W., et al., Cell
75:805 816 (1993)), where their involvement in the regulation of
cell growth is better understood.
mdm2, a known oncogene, was originally found on mouse double minute
chromosomes (Cahilly-Snyder., L., et al., Somatic Cell Mol. Genet.
13:235 244 (1987)). Its protein product was subsequently found to
form a complex with p53, which was first observed in a rat
fibroblast cell line (Clone 6) previously transfected with a
temperature sensitive mouse p53 gene (Michalovitz, D., et al., Cell
62:671 680 (1990)). The rat cell line grew well at 37.degree. C.
but exhibited a G1 arrest when shifted down to 32.degree. C., which
was entirely consistent with an observed temperature dependent
switch in p53 conformation and activity. However, the p53-MDM2
complex was only observed in abundance at 32.degree. C., at which
temperature p53 was predominantly in a functional or "wild-type"
form (Barak, Y. et al., EMBO J. 11:2115 2121 (1992) and Momand, J.,
et al., Cell 69:1237 1245 (1992)). By shifting the rat cell line
down to 32.degree. C. and blocking de novo protein synthesis it was
shown that only "wild-type" p53 induced expression of the mdm2
gene, thereby accounting for the differential abundance of the
complex in terms of p53 transcriptional activity (Barak, Y., et
al., EMBO J. 12:461 468 (1993)). The explanation was further
developed by the identification of a DNA binding site for wild-type
p53 within the first intron of the mdm2 gene (Wu, X., et al., Genes
Dev. 7:1126 1132 (1993)). Reporter constructs employing this p53
DNA binding site revealed that they were inactivated when wild-type
p53 was co-expressed with MDM2.
This inhibition of the transcriptional activity of p53 may be
caused by MDM2 blocking the activation domain of p53 and/or the DNA
binding site. Consequently, it was proposed that mdm2 expression is
autoregulated, via the inhibitory effect of MDM2 protein on the
transcriptional activity of wild-type p53. This p53-mdm2
autoregulatory feedback loop provided a novel insight as to how
cell growth might be regulated by p53. Up to a third of human
sarcomas are considered to overcome p53-regulated growth control by
amplification of the hdm2 gene (the human homologue of mdm2)
(Oliner, J. D., et al., Nature 358:80 83 (1992)). Hence, the
interaction between p53 and HDM2 represents a key potential
therapeutic target. One mechanism by which MDM2 can promote
tumorogenesis is by its inhibitory action on p53. The tumor
suppressor functions of p53 control a pivotal checkpoint in the
control of cell cycling (reviewed in Levine, A. J., Cell 88:323 331
(1997)). p53 is a transcription factor for a number of proteins
that cause cell cycle arrest or cell death by apoptosis. The level
and transcriptional activity of p53 are increased by damage to
cellular DNA. The MDM2 protein inhibits p53 function by binding to
an amphipathic N-terminal helix of p53, abrogating the interaction
of p53 with other proteins and its transactivation activity. The
interaction with MDM2 also targets p53 for ubiquitin dependent
protein degradation. MDM2 exhibits p53 independent effects on cell
cycling as well, possibly by direct interaction with some of the
downstream effectors such as pRB and EF2 (Reviewed in Zhang, R. and
Wang, H., Cur. Pharm. Des. 6:393 416 (2000)).
Blocking HDM2 from binding p53 would be therapeutically useful in
restoring cell cycle control to cells that overexpress HDM2 as a
front line cancer treatment. More generally, inhibition of HDM2 may
increase the effectiveness of chemotherapy and radiation in p53
normal cancers by enhancing apoptosis and growth arrest signaling
pathways.
A need continues to exist for potent, small molecules that inhibit
the interactions between HDM2 and p53.
SUMMARY OF THE INVENTION
A first aspect of the present invention is directed to novel
compounds of Formula I.
A second aspect of the present invention is directed to
pharmaceutical compositions comprising at least one compound of
Formula I, or a salt thereof, and one or more pharmaceutically
acceptable excipients.
A third aspect of the present invention is directed to a method of
inhibiting the binding of a protein encoded by hdm2 to p53 protein,
comprising contacting p53 or one or more proteins encoded by mdm2,
with one or more compounds of Formula I.
A fourth aspect of the invention is directed to a method of
inducing apoptosis, comprising contacting an animal with a
composition comprising a pharmaceutically effective amount of at
least one compound of Formula I, or a salt thereof, and one or more
pharmaceutically-acceptable excipients.
A fifth aspect of the present invention is directed to a method of
treating cancer. The method comprises contacting an animal with (a)
a pharmaceutically effective amount of an antineoplastic agent and
(b) a pharmaceutically effective amount of at least one compound of
Formula I, or a salt thereof, and one or more
pharmaceutically-acceptable excipients.
A sixth aspect of the present invention is directed to a method of
treating cancer, comprising contacting an animal with a composition
comprising (a) a pharmaceutically effective amount of at least one
compound of Formula I, or a salt thereof, (b) one or more agents
that induce or cause DNA damage, and (c) one or more
pharmaceutically-acceptable excipients.
A seventh aspect of the present invention is directed to a method
of synthesizing compounds of Formula I.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
A novel class of small molecules that bind to HDM2 and/or MDM2 has
now been discovered. By interfering with HDM2-p53 or MDM2-p53
interactions, these compounds increase the intracellular
concentration of p53. These small molecules, therefore, have
therapeutic utility in sensitizing tumor cells for chemotherapy. In
tumor types particularly sensitive to an increase in functional
p53, compounds of this type will be sufficient to induce apoptosis.
Compounds of the present invention are also useful in treating
tumor types in which HDM2 or MDM2 is overexpressed.
Compounds of the present invention include compounds of Formula
I:
##STR00002## or a solvate, hydrate or pharmaceutically acceptable
salt thereof; wherein:
X and Y are independently --C(O)--, --CH.sub.2-- or --C(S)--;
R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently hydrogen,
halo, alkyl, alkenyl, alkynyl, cycloalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
heteroaryl, optionally substituted heteroaralkyl, alkoxy,
optionally substituted aryloxy, optionally substituted
heteroaryloxy, cyano, amino, alkanoylamino, nitro, hydroxy,
carboxy, or alkoxycarbonyl;
or R.sup.1 and R.sup.2, or R.sup.2 and R.sup.3, or R.sup.3 and
R.sup.4 are taken together to form --(CH.sub.2).sub.u--, where u is
3 6, --CH.dbd.CH--CH.dbd.CH-- or --CH.sub.2CH.dbd.CHCH.sub.2--;
R.sup.5 is hydrogen, alkyl, cycloalkyl, optionally substituted
aryl, optionally substituted heteroaryl, optionally substituted
aralkyl, optionally substituted heteroaralkyl, carboxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, aminocarbonyl,
aminocarbonylalkyl, alkylaminocarbonyl or
alkylaminocarbonylalkyl;
R.sup.6 is cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, aralkyl,
heteroarylalkyl, or a saturated or partially unsaturated
heterocycle, each of which is optionally substituted;
R.sup.7 and R.sup.8 are independently hydrogen or alkyl;
R.sup.9 is cycloalkyl, aryl, heteroaryl, a saturated or partially
unsaturated heterocycle, cycloalkyl(alkyl), aralkyl or
heteroarylalkyl, each of which is optionally substituted; and
R.sup.10 is --(CH.sub.2).sub.n--CO.sub.2R.sup.b,
--(CH.sub.2).sub.m--CO.sub.2M, --(CH.sub.2).sub.1--OH or
--(CH.sub.2).sub.j--CONR.sup.cR.sup.d where R.sup.b is hydrogen,
alkyl, optionally substituted cycloalkyl, or optionally
substituted, saturated or partially unsaturated heterocycle; M is a
cation; R.sup.c and R.sup.d are independently hydrogen, alkyl,
hydroxyalkyl, carboxyalkyl, aminoalkyl, optionally substituted
cycloalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, and an optionally substituted, saturated or
partially unsaturated heterocycle; and
n is 0 8, m is 0 8, i is 1 8 and j is 0 8.
Preferred compounds include compounds of Formula I, or salts
thereof, wherein:
R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently hydrogen,
halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-7 cycloalkyl, optionally substituted C.sub.6-10 aryl,
optionally substituted C.sub.6-10 ar(C.sub.1-6)alkyl, optionally
substituted heteroaryl, optionally substituted
heteroar(C.sub.1-6)alkyl, C.sub.1-6 alkoxy, optionally substituted
C.sub.6-10 aryloxy, optionally substituted heteroaryloxy, cyano,
amino, alkanoylamino, nitro, hydroxy, carboxy, or C.sub.1-6
alkoxycarbonyl;
or R.sup.1 and R.sup.2, or R.sup.2 and R.sup.3, or R.sup.3 and
R.sup.4 are taken together to form --CH.dbd.CH--CH.dbd.CH-- or
--CH.sub.2CH.dbd.CHCH.sub.2--;
R.sup.5 is hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl,
optionally substituted C.sub.6-10 aryl, optionally substituted
heteroaryl, optionally substituted C.sub.6-10 ar(C.sub.1-6)alkyl,
optionally substituted heteroar(C.sub.1-6)alkyl,
carboxy(C.sub.1-6)alkyl, C.sub.1-6 alkoxycarbonyl, C.sub.1-6
alkoxycarbonyl(C.sub.1-6)alkyl, aminocarbonyl,
aminocarbonyl(C.sub.1-6)alkyl, or C.sub.1-6
alkylaminocarbonyl(C.sub.1-6)alkyl;
R.sup.6 is C.sub.3-7 cycloalkyl, C.sub.6-10 aryl, heteroaryl, a
saturated or partially unsaturated heterocycle, C.sub.3-7
cycloalkyl(C.sub.1-6)alkyl, C.sub.6-10 ar(C.sub.1-6)alkyl or
heteroaryl(C.sub.1-6)alkyl, each of which is optionally ring
substituted by one or more substituents independently selected from
the group consisting of C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, C.sub.6-10 aryl, phenoxy, benzyloxy, 5 10
membered heteroaryl, hydroxy, C.sub.1-4 alkoxy, C.sub.1-4
alkylenedioxy, halo, C.sub.1-4 haloalkyl, C.sub.1-4 alkylthio,
thio, amino, mono(C.sub.1-4)alkylamino, di(C.sub.1-4)alkylamino,
and nitro;
R.sup.7 is hydrogen or C.sub.1-6 alkyl;
R.sup.8 is hydrogen or C.sub.1-6 alkyl;
R.sup.9 is C.sub.3-7 cycloalkyl, a saturated or partially
unsaturated heterocycle, C.sub.6-10 aryl, heteroaryl, C.sub.3-7
cycloalkyl(C.sub.1-6)alkyl, C.sub.6-10 ar(C.sub.1-6)alkyl or
heteroaryl(C.sub.1-6)alkyl, each of which is optionally substituted
by one or more substituents independently selected from the group
consisting of C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, C.sub.6-10 aryl, 5 10 membered heteroaryl, hydroxy,
C.sub.1-4 alkoxy, C.sub.1-4 alkylenedioxy, carboxy, halo, C.sub.1-4
haloalkyl, trifluoromethoxy, C.sub.1-4 alkylthio, thio, amino,
mono(C.sub.1-4)alkylamino, di(C.sub.1-4)alkylamino, and nitro;
and
R.sup.10 is --(CH.sub.2).sub.n--CO.sub.2R.sup.b,
--(CH.sub.2).sub.m--CO.sub.2M, --(CH.sub.2).sub.i--OH or
--(CH.sub.2).sub.j--CONR.sup.cR.sup.d, where R.sup.b is hydrogen,
C.sub.1-6 alkyl, optionally substituted C.sub.3-7 cycloalkyl, or an
optionally substituted, saturated or partially unsaturated
heterocycle; M is a cation; R.sup.c and R.sup.d are independently
hydrogen, C.sub.1-6 alkyl, C.sub.1-6 hydroxyalkyl, C.sub.1-6
carboxyalkyl, aminoalkyl, optionally substituted C.sub.3-7
cycloalkyl, optionally substituted C.sub.6-10 aryl, optionally
substituted C.sub.6-10 ar(C.sub.1-6)alkyl, optionally substituted
heteroaryl, optionally substituted heteroaryl(C.sub.1-6)alkyl, or
an optionally substituted, saturated or partially unsaturated
heterocycle; and
n is 0 4, m is 0 4, i is 1 4 and j is 0 4.
In one preferred embodiment:
R.sup.1 and R.sup.4 are both hydrogen;
R.sup.2 is hydrogen, halo, C.sub.1-6 alkyl, C.sub.1-6 hydroxyalkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl,
acetylamino, cyano, amino, C.sub.1-6 alkoxy, phenyl, thienyl,
furanyl, and pyrrolyl, wherein said phenyl, thienyl and furanyl are
optionally substituted by one or more substituents independently
selected from the group consisting of halo, C.sub.1-4 alkoxy,
C.sub.1-4 alkyl, amino, methylenedioxy, and ethylenedioxy;
R.sup.3 is hydrogen, C.sub.1-6 alkyl, phenyl, or halo; or R.sup.2
and R.sup.3 are taken together to form
--CH.dbd.CH--CH.dbd.CH--;
R.sup.5 is hydrogen; C.sub.1-6 alkyl; C.sub.1-6 hydroxyalkyl;
carboxy(C.sub.1-6)alkyl; C.sub.1-6 alkylcarbamoyl(C.sub.1-6)alkyl;
C.sub.1-6 alkoxycarbonylamino(C.sub.1-6)alkyl; C.sub.3-7
cycloalkyl(C.sub.1-6)alkyl; C.sub.6-10 aryl, optionally substituted
by C.sub.1-4 alkyl or halo; C.sub.6-10 ar(C.sub.1-4)alkyl
optionally substituted by C.sub.1-4 alkyl or halo; and
pyridyl(C.sub.1-4)alkyl;
R.sup.6 is C.sub.6-10 aryl, thienyl, benzothienyl, furanyl,
benzofuranyl, indolyl, pyridyl, quinolinyl, C.sub.3-7 cycloalkenyl
or cubanyl, each of which is optionally substituted by one or more
substituents independently selected from the group consisting of
halo, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.1-4 alkoxy,
halo(C.sub.1-4)alkoxy, trifluoromethyl, trifluoromethoxy, C.sub.1-4
alkylsulfanyl, trifluoromethylsulfanyl, cyano, thienyl, phenyl,
halophenyl, trifluoromethylphenyl, phenoxy, benzyloxy and
pyrrolidinyl;
R.sup.7 is hydrogen or C.sub.1-6 alkyl;
R.sup.8 is hydrogen or C.sub.1-6 alkyl;
R.sup.9 is C.sub.3-7 cycloalkyl, C.sub.6-10 aryl, heteroaryl,
C.sub.3-7 cycloalkyl(C.sub.1-6)alkyl, C.sub.6-10 ar(C.sub.1-6)alkyl
or heteroaryl(C.sub.1-6)alkyl, each of which is optionally
substituted on the ring portion; and
R.sup.10 is --(CH.sub.2).sub.n--CO.sub.2R.sup.b or
--(CH.sub.2).sub.m--CO.sub.2M, where R.sup.b is hydrogen, C.sub.1-6
alkyl, optionally substituted C.sub.3-7 cycloalkyl, or optionally
substituted heterocycloalkyl, M is a cation n and m are
independently 0, 1, 2, 3 or 4; or
R.sup.10 is --(CH.sub.2).sub.i--OH or
--(CH.sub.2).sub.j--CONR.sup.cR.sup.d, where R.sup.cand R.sup.d are
independently hydrogen, hydroxy, C.sub.3-7 cycloalkyl, C.sub.1-6
alkyl, C.sub.1-6 hydroxyalkyl, C.sub.1-6 carboxyalkyl, C.sub.1-6
aminoalkyl, optionally substituted phenyl, or optionally
substituted benzyl; and i is 1, 2, 3, or 4, and j is 0, 1, 2, 3 or
4.
Preferred compounds include those wherein R.sup.1 is hydrogen.
Preferred compounds include those wherein R.sup.4 is hydrogen.
Useful values of R.sup.2 include hydrogen, halo, C.sub.1-4 alkyl,
C.sub.3-7 cycloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
acetylamino, C.sub.1-6 alkoxy, phenyl, halophenyl, hydroxyphenyl,
C.sub.1-6 alkoxyphenyl, C.sub.1-6 alkylphenyl, aminophenyl,
C.sub.1-6 alkylenedioxyphenyl, hydroxycarbonylphenyl, thienyl,
C.sub.1-6 alkylthienyl, furanyl, pyrrolyl, amino, C.sub.1-6
hydroxyalkyl and cyano.
Useful values of R.sup.2 also include hydrogen, iodo, fluoro,
chloro, bromo, methyl, ethyl, propyl, isopropyl, t-butyl,
sec-butyl, cyclopropyl, ethynyl, acetylamino, methoxy, phenyl,
3-chlorophenyl, 4-chlorophenyl, 4-hydroxyphenyl, 3-methoxyphenyl,
4-methylphenyl, 3-methylphenyl, 3-isopropylphenyl, 3-aminophenyl,
3,4-methylenedioxyphenyl, 4-hydroxycarbonylphenyl, thien-3-yl,
4-methylthien-2-yl, furan-2-yl, 1H-pyrrol-3-yl, amino,
2-hydroxyethyl, hydroxymethyl, furan-3-yl, vinyl and cyano.
Preferred compounds include those wherein R.sup.2 is halo or
phenyl. More preferred compounds include those wherein R.sup.2 is
iodo.
Useful values of R.sup.3 include hydrogen, phenyl, fluoro, chloro,
iodo and methyl. Preferred compounds are those wherein R.sup.3 is
hydrogen.
Useful values of R.sup.5 include hydrogen, C.sub.1-6 alkyl,
C.sub.1-6 hydroxyalkyl, carboxy(C.sub.1-6)alkyl, C.sub.1-6
alkylphenyl, C.sub.1-6 alkylbenzyl, phenethyl,
phenyl(C.sub.1-6)alkyl, naphthyl(C.sub.1-6)alkyl, C.sub.3-7
cycloalkyl(C.sub.1-6)alkyl, pyridyl(C.sub.1-6)alkyl, C.sub.1-6
alkoxycarbonylamino(C.sub.1-6)alkyl, and C.sub.1-6
alkylcarbamoyl(C.sub.1-6)alkyl.
Useful values of R.sup.5 also include hydrogen, methyl,
carboxymethyl, 3-methylbutyl, 2-methylpropyl, isopropyl,
2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, benzyl,
phenethyl, 3-phenylpropyl, naphthalen-2-ylmethyl, cyclohexylmethyl,
cyclopentylmethyl, cyclobutylmethyl, pyrid-2-ylmethyl,
pyrid-3-ylmethyl, pyrid-4-ylmethyl, 2-methylbenzyl, 3-methylbenzyl,
4-methylbenzyl, 2-carboxyethyl, 2-t-butoxycarbonylaminoethyl,
2-pyrid-2-ylethyl, methylcarbamoylmethyl and
2,3-dihydroxypropyl.
Preferred compounds include those wherein R.sup.5 is hydrogen.
Useful values of R.sup.6 include optionally substituted C.sub.6-10
aryl.
Useful values of R.sup.6 also include trifluoromethylphenyl,
halophenyl, C.sub.1-6 alkylphenyl, C.sub.1-6 alkoxyphenyl,
halo(C.sub.1-4)alkoxyphenyl, naphthyl, benzyloxyphenyl,
phenoxyphenyl, dihydrobenzodioxinyl, trifluoromethylhalophenyl,
pyridyl, thienyl, C.sub.1-6 alkylthienyl, halothienyl, bithienyl,
C.sub.1-6 alkylbenzothienyl, (halophenyl)furanyl, quinolinyl,
biphenyl, indolyl, (trifluoromethylsulfanyl)phenyl,
(trifluoromethylphenyl)furanyl, halo(C.sub.1-4)alkoxyphenyl,
benzofuranyl, cyanophenyl, halopyridyl, (methylsulfanyl)phenyl,
pyrrolidinylphenyl, C.sub.2-6 alkenyl(C.sub.3-7)cycloalkenyl,
cubanyl and halocubanyl.
Useful values of R.sup.6 also include 2-trifluoromethylphenyl,
3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-chlorophenyl,
3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl,
4-bromophenyl, 4-iodophenyl, 4-methylphenyl, 4-ethylphenyl,
4-trifluoromethoxyphenyl, 4-isopropylphenyl, phenyl,
4-methoxy-phenyl, naphthalen-2-yl, 4-tert-butylphenyl,
4-benzyloxyphenyl, 4-phenoxyphenyl, 3,4-dichlorophenyl,
3,4-dimethoxyphenyl, 2,3-dihydrobenzo[1,4]dioxin-6-yl,
4-bromo-2-fluorophenyl, 2-fluoro-4-trifluoromethylphenyl,
3-fluoro-4-trifluoromethylphenyl, 4-chloro-3-trifluoromethylphenyl,
4-chloro-3-fluorophenyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl,
thien-3-yl, 5-methylthien-2-yl, 3-methylthien-2-yl,
4-bromothien-2-yl, 5-[2,2']bithienyl,
3-methylbenzo[b]thiophen-2-yl, 5-(2-chlorophenyl)-furan-2-yl,
5-(3-chlorophenyl)-furan-2-yl, quinolin-3-yl, biphen-4-yl,
indol-2-yl, indol-3-yl, 4-trifluoromethylsulfanylphenyl,
5-(3-trifluoromethylphenyl)furan-2-yl,
4-(1,1,2,2-tetrafluoroethoxy)phenyl, 4-difluoromethoxyphenyl,
benzofuran-2-yl, 4-cyanophenyl, 6-chloropyrid-3-yl,
4-methylsulfanylphenyl, 4-pyrrolidin-1-ylphenyl,
5-chlorothien-2-yl, 4-isopropenylcyclohex-1-enyl and
1-chlorocuban-4-yl.
Preferred compounds include those wherein R.sup.6 is
4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl or
4-trifluoromethoxyphenyl. More preferred compounds include those
wherein R.sup.6 is 4-chlorophenyl.
Useful values of R.sup.7 include hydrogen and methyl. Preferred
compounds include those wherein R.sup.7 is hydrogen.
Useful values of R.sup.8 include hydrogen and methyl. Preferred
compounds include those wherein R.sup.8 is hydrogen.
Useful values of R.sup.9 include optionally substituted C.sub.6-10
aryl and optionally substituted C.sub.6-10 ar(C.sub.1-6)alkyl.
Useful values of R.sup.9 also include phenyl, 4-chlorophenyl,
4-chlorobenzyl, benzyl, cyclohexyl, cyclohexylmethyl,
4-hydroxyphenyl, pyridylmethyl, 4-fluorophenyl,
4-trifluoromethylphenyl, 4-iodobenzyl, 4-bromobenzyl, thien-2-yl,
thien-2-ylmethyl, naphth-2-ylmethyl, pyrid-2-ylethyl,
3-methylphenyl, 4-methylphenyl, 4-ethylphenyl,
4-chloro-3-fluorophenyl, 2-fluoro-4-trifluoromethylphenyl,
4-hydroxycarbonylphenyl, naphthalen-2-yl, naphthalen-1-yl,
4-iodophenyl, 4-bromophenyl, 3,4-dichlorophenyl, 2-chlorophenyl,
4-tert-butylphenyl, 4-isopropylphenyl, 3-chlorophenyl,
4-trifluoromethoxyphenyl, and 3-hydroxyphenyl, 4-hydroxybenzyl,
4-trifluoromethylbenzyl, naphth-1-ylmethyl, 6-chloropyrid-3-yl and
6-methylpyrid-3-yl.
Preferred compounds include those wherein R.sup.9 is halophenyl or
halobenzyl. More preferred compounds include those wherein R.sup.9
is phenyl or 4-chlorophenyl.
Useful values of R.sup.10 include --COOR.sup.b and
--CH.sub.2--COOR.sup.b, where R.sup.b is hydrogen or C.sub.1-6
alkyl; and --COOM and --CH.sub.2--COOM, where M is Na.sup.+ or
K.sup.+.
Preferred compounds include those wherein R.sup.10 is --COOR.sup.b
or --CH.sub.2--COOR.sup.b, where R.sup.b is hydrogen, methyl,
ethyl, propyl or tert-butyl.
Preferred compounds also include those wherein R.sup.10 is --COOH
or --COOM, where M is Na.sup.30 or K.sup.+.
Useful values of R.sup.10 also include --CH.sub.2OH and
--CH.sub.2CH.sub.2OH; and --CH.sub.2--CONR.sup.cR.sup.d and
--CONR.sup.cR.sup.d, where R.sup.c and R.sup.d are independently
hydrogen, methyl, ethyl, propyl, t-butyl, hydroxymethyl,
hydroxyethyl, hydroxypropyl, aminomethyl, aminoethyl, aminopropyl,
carboxymethyl, carboxyethyl, carboxypropyl, cyclopentyl,
cyclohexyl, phenyl or benzyl.
Preferred compounds include those wherein R.sup.10 is
--CH.sub.2--CONR.sup.cR.sup.d or --CONR.sup.cR.sup.d, where R.sup.c
and R.sup.d are independently hydrogen, methyl, hydroxyethyl,
3-carboxypropyl, 1-carboxy-2-methylpropyl, hydroxy, 4-carboxybutyl,
5-carboxypentyl, 2-(methoxycarbonyl)ethyl or
2-(hydroxyguanidino)ethyl.
In each of the above embodiments, X and Y are independently
--C(O)--, --CH.sub.2-- or --C(S)--, more preferably --C(O)-- or
--C(S)--, most preferably --C(O)--.
A second aspect of the present invention is directed to
pharmaceutical compositions comprising
a) at least one compound of Formula I or a pharmaceutically
acceptable salt thereof; and
b) one or more pharmaceutically-acceptable excipients.
Preferably, the pharmaceutical composition is sterile.
A third aspect of the present invention is directed to a method of
inhibiting the binding of a protein encoded by mdm2 to p53 protein,
comprising contacting p53 or one or more proteins encoded by mdm2
with one or more compounds of Formula I, wherein R.sup.1 R.sup.10
are defined as above.
A fourth aspect of the invention is directed to a method of
inducing apoptosis, comprising contacting an animal with a
composition comprising a pharmaceutically effective amount of at
least one compound of Formula I, or a salt thereof, wherein R.sup.1
R.sup.10 are defined as above, and optionally one or more
pharmaceutically-acceptable excipients.
A fifth aspect of the present invention is directed to a method of
treating cancer, comprising contacting an animal with (a) a
pharmaceutically effective amount of an antineoplastic agent, and
(b) a pharmaceutically effective amount of at least one compound of
Formula I, or a salt thereof, wherein R.sup.1 R.sup.10, are defined
as above, and optionally one or more pharmaceutically-acceptable
excipients, in combination with (a), (b), or (a) and (b).
A sixth aspect of the present invention is directed to a method of
treating cancer, comprising contacting an animal with a composition
comprising (a) a pharmaceutically effective amount of at least one
compound of Formula I, or a salt thereof, (b) one or more agents
that induce or cause DNA damage, and optionally (c) one or more
pharmaceutically-acceptable excipients.
A seventh aspect of the present invention is directed to a method
of making compounds of Formula I.
Compounds within the scope of the invention are described in the
Examples. Examples of preferred compounds include:
(4-chloro-phenyl)-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydr-
o-benzo[e][1,4]diazepin-4-yl]-acetic acid;
2-[7-bromo-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]-
diazepin-4-yl]-3-(4-chloro-phenyl)-propionic acid;
2-(4-chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetra-
hydro-benzo[e][1,4]diazepin-4-yl]-acetamide;
[7-chloro-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]d-
iazepin-4-yl]-(4-chloro-phenyl)-acetic acid;
(4-chloro-phenyl)-[3-(4-chloro-phenyl)-7-ethynyl-2,5-dioxo-1,2,3,5-tetrah-
ydro-benzo[e][1,4]diazepin-4-yl]-acetic acid;
[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]dia-
zepin-4-yl]-p-tolyl-acetic acid;
(4-chloro-3-fluoro-phenyl)-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5--
tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid;
(4-chloro-phenyl)-[3-(4-chloro-phenyl)-7-ethyl-2,5-dioxo-1,2,3,5-tetrahyd-
ro-benzo[e][1,4]diazepin-4-yl]-acetic acid;
(4-chloro-phenyl)-[3-(4-chloro-phenyl)-7-isopropyl-2,5-dioxo-1,2,3,5-tetr-
ahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid;
(4-bromo-phenyl)-[3-(4-chloro-phenyl)-7-isopropyl-2,5-dioxo-1,2,3,5-tetra-
hydro-benzo[e][1,4]diazepin-4-yl]-acetic acid;
[3-(4-chloro-3-fluoro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e-
][1,4]diazepin-4-yl]-(4-chloro-phenyl)-acetic acid;
[3-(4-chlorophenyl)-7-phenyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]di-
azepin-4-yl]-phenylacetic acid;
[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]dia-
zepin-4-yl]-(4-fluoro-phenyl)-acetic acid;
[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]dia-
zepin-4-yl]-(4-trifluoromethyl-phenyl)-acetic acid;
(4-chloro-phenyl)-[7-iodo-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-
-tetrahydrobenzo[e][1,4]diazepin-4-yl]-acetic acid;
(4-chloro-phenyl)-[7-iodo-2,5-dioxo-3-(4-trifluoromethyl-phenyl)-1,2,3,5--
tetrahydrobenzo[e][1,4]diazepin-4-yl]-acetic acid;
[3-(4-bromo-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diaz-
epin-4-yl]-(4-chloro-phenyl)-acetic acid;
[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]dia-
zepin-4-yl]-(4-isopropyl-phenyl)-acetic acid;
(4-chloro-phenyl)-[3-(4-chloro-phenyl)-7-cyano-2,5-dioxo-1,2,3,5-tetrahyd-
ro-benzo[e][1,4]diazepin-4-yl]-acetic acid;
3-(4-chloro-phenyl)-4-(3-hydroxy-1-phenyl-propyl)-7-iodo-3,4-dihydro-1H-b-
enzo[e][1,4]diazepine-2,5-dione;
2-(4-chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetra-
hydro-benzo[e][1,4]diazepin-4-yl]-N-hydroxy-acetamide;
[7-bromo-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]di-
azepin-4-yl]-(4-chloro-phenyl)-acetic acid;
[8-chloro-3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e-
][1,4]diazepin-4-yl]-(4-chloro-phenyl)-acetic acid;
5-{2-(4-chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-te-
trahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino }-pentanoic
acid;
3-{2-(4-chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-te-
trahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino }-propionic
acid;
5-[4-[carboxy-(4-chloro-phenyl)-methyl]-3-(4-chloro-phenyl)-7-iodo-2,5-di-
oxo-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-yl]-pentanoic
acid;
and pharmaceutically acceptable salts thereof.
Additional examples of preferred compounds include:
(4-chlorophenyl)-[3-(4-chlorophenyl)-7-iodo-5-oxo-1,2,3,5-tetrahydro-benz-
o[e][1,4]diazepin-4-yl]acetic acid;
3-(4-chloro-phenyl)-3-[3-(4-chloro-phenyl)-7-iodo-5-oxo-1,2,3,5-tetrahydr-
o-benzo[e][1,4]diazepin-4-yl]-propionic acid;
(4-chloro-phenyl)-[3-(4-chloro-phenyl)-7-iodo-5-oxo-2-thioxo-1,2,3,5-tetr-
ahydro-benzo[e][1,4]diaze pin-4-yl]-acetic acid;
3-(4-chloro-phenyl)-4-[1-(4-chloro-phenyl)-2-hydroxy-ethyl]-7-iodo-1,3,4,-
5-tetrahydro-benzo[e][1,4]diazepin-2-one;
3-(4-chloro-phenyl)-4-[1-(4-chloro-phenyl)-2-hydroxy-ethyl]-7-iodo-1,2,3,-
4-tetrahydro-benzo[e][1,4]diazepin-5-one;
and pharmaceutically-acceptable salts thereof.
The invention disclosed herein is also meant to encompass the in
vivo metabolic products of the disclosed compounds. Such products
may result for example from the oxidation, reduction, hydrolysis,
amidation, esterification and the like of the administered
compound, primarily due to enzymatic processes. Accordingly, the
invention includes compounds produced by a process comprising
contacting a compound of this invention with a mammal for a period
of time sufficient to yield a metabolic product thereof. Such
products typically are identified by preparing a radiolabeled
compound of the invention, administering it parenterally in a
detectable dose to an animal such as rat, mouse, guinea pig,
monkey, or to man, allowing sufficient time for metabolism to occur
and isolating its conversion products from the urine, blood or
other biological samples.
Some of the compounds disclosed herein may contain one or more
asymmetric centers and thus give rise to enantiomers,
diastereomers, and other stereoisomeric forms. The present
invention is also meant to encompass all such possible forms as
well as their racemic and resolved forms and mixtures thereof. When
the compounds described herein contain olefinic double bonds or
other centers of geometric asymmetry, and unless specified
otherwise, it is intended to include both E and Z geometric
isomers. All tautomers are intended to be encompassed by the
present invention as well.
As used herein, the term "stereoisomers" is a general term for all
isomers of individual molecules that differ only in the orientation
of their atoms in space. It includes enantiomers and isomers of
compounds with more than one chiral center that are not mirror
images of one another (diastereomers).
The term "chiral center" refers to a carbon atom to which four
different groups are attached, or a sulfur atom to which three
different groups are attached, where the sulfur atom and its
attached groups form a sulfoxide, sulfinic ester, sulfonium salt or
sulfite.
The term "enantiomer" or "enantiomeric" refers to a molecule that
is nonsuperimposable on its mirror image and hence optically active
wherein the enantiomer rotates the plane of polarized light in one
direction and its mirror image rotates the plane of polarized light
in the opposite direction.
The term "racemic" refers to a mixture of equal parts of
enantiomers and which is optically inactive.
The term "resolution" refers to the separation or concentration or
depletion of one of the two enantiomeric forms of a molecule. The
phrase "enantiomeric excess" refers to a mixture wherein one
enantiomer is present is a greater concentration than its mirror
image molecule.
The compounds of Formula I may also be solvated, especially
hydrated. Hydration may occur during manufacturing of the compounds
or compositions comprising the compounds, or the hydration may
occur over time due to the hygroscopic nature of the compounds.
Certain compounds within the scope of Formula I are derivatives
referred to as "prodrugs." The expression "prodrug" denotes a
derivative of a known direct acting drug, which derivative has
enhanced delivery characteristics and therapeutic value as compared
to the drug, and is transformed into the active drug by an
enzymatic or chemical process. Prodrugs are derivatives of the
compounds of the invention which have metabolically cleavable
groups and become by solvolysis or under physiological conditions
the compounds of the invention which are pharmaceutically active in
vivo. For example, ester derivatives of compounds of this invention
are often active in vivo, but not in vitro. Other derivatives of
the compounds of this invention have activity in both their acid
and acid derivative forms, but the acid derivative form often
offers advantages of solubility, tissue compatibility, or delayed
release in the mammalian organism (see, Bundgard, H., Design of
Prodrugs, pp. 7 9, 21 24, Elsevier, Amsterdam 1985). Prodrugs
include acid derivatives well known to practitioners of the art,
such as, for example, esters prepared by reaction of the parent
acid with a suitable alcohol, or amides prepared by reaction of the
parent acid compound with an amine. Simple aliphatic or aromatic
esters derived from acidic groups pendent on the compounds of this
invention are preferred prodrugs. In some cases it is desirable to
prepare double ester type prodrugs such as (acyloxy) alkyl esters
or ((alkoxycarbonyl)oxy)alkyl esters. Useful prodrugs are those
where R.sup.b is alkyl, alkenyl, alkynyl, or arylalkyl.
When any variable occurs more than one time in any constituent or
in Formula I, its definition on each occurrence is independent of
its definition at every other occurrence. Also, combinations of
substituents and/or variables are permissible only if such
combinations result in stable compounds.
DEFINITIONS
The term "alkyl" as employed herein by itself or as part of another
group refers to both straight and branched chain radicals of up to
10 carbons, unless the chain length is otherwise limited, such as
methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl,
hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,
2,2,4-trimethylpentyl, nonyl, or decyl.
The term "alkenyl" is used herein to mean a straight or branched
chain radical of 2 10 carbon atoms, unless the chain length is
otherwise limited, wherein there is at least one double bond
between two of the carbon atoms in the chain, including, but not
limited to, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl,
1-butenyl, 2-butenyl, and the like. Preferably, the alkenyl chain
is 2 to 8 carbon atoms in length, most preferably from 2 to 4
carbon atoms in length.
The term "alkynyl" is used herein to mean a straight or branched
chain radical of 2 10 carbon atoms, unless the chain length is
otherwise limited, wherein there is at least one triple bond
between two of the carbon atoms in the chain, including, but not
limited to, ethynyl, 1-propynyl, 2-propynyl, and the like.
Preferably, the alkynyl chain is 2 to 8 carbon atoms in length,
most preferably from 2 to 4 carbon atoms in length.
In all instances herein where there is an alkenyl or alkynyl moiety
as a substituent group, the unsaturated linkage, i.e., the vinyl or
ethenyl linkage, is preferably not directly attached to a nitrogen,
oxygen or sulfur moiety.
The term "alkoxy" or "alkyloxy" refers to any of the above alkyl
groups linked to an oxygen atom. Typical examples are methoxy,
ethoxy, isopropyloxy, sec-butyloxy, and t-butyloxy.
The term "aryl" as employed herein by itself or as part of another
group refers to monocyclic or bicyclic aromatic groups containing
from 6 to 12 carbons in the ring portion, preferably 6 10 carbons
in the ring portion. Typical examples include phenyl, biphenyl,
naphthyl or tetrahydronaphthyl.
The term "aralkyl" or "arylalkyl" as employed herein by itself or
as part of another group refers to C.sub.1-6 alkyl groups as
discussed above having an aryl substituent, such as benzyl,
phenylethyl or 2-naphthylmethyl.
The term "heteroaryl" as employed herein refers to groups having 5
to 14 ring atoms; 6, 10 or 14 pi electrons shared in a cyclic
array; and containing carbon atoms and 1, 2, 3, or 4 oxygen,
nitrogen or sulfur heteroatoms (where examples of heteroaryl groups
are: thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl,
furyl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl,
xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl,
pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl,
4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl,
naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl,
4.alpha.H-carbazolyl, carbazolyl, .beta.-carbolinyl,
phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl,
phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl,
phenoxazinyl, and tetrazolyl groups).
The phrase "saturated or partially unsaturated heterocycle" as
employed herein, by itself or as part of another group, refers to a
saturated or partially unsaturated ring system having 5 to 14 ring
atoms selected from carbon atoms and 1, 2, 3, or 4 oxygen,
nitrogen, or sulfur heteroatoms. Typical saturated examples include
pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl,
tetrahydropyranyl, piperidyl, piperazinyl, quinuclidinyl,
morpholinyl, and dioxacyclohexyl. Typical partially unsaturated
examples include pyrrolinyl, imidazolinyl, pyrazolinyl,
dihydropyridinyl, tetrahydropyridinyl, and dihydropyranyl. Either
of these systems can be optionally fused to a benzene ring.
The terms "heteroarylalkyl" or "heteroaralkyl" as employed herein
both refer to a heteroaryl group attached to an alkyl group.
Typical examples include 2-(3-pyridyl)ethyl, 3-(2-furyl)-n-propyl,
3-(3-thienyl)-n-propyl, and 4-(1-isoquinolinyl)-n-butyl.
The term "cycloalkyl" as employed herein by itself or as part of
another group refers to cycloalkyl groups containing 3 to 9 carbon
atoms. Typical examples are cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl.
The term "cycloalkylalkyl" or "cycloalkyl(alkyl)" as employed
herein, by itself or as part of another group, refers to a
cycloalkyl group attached to an alkyl group. Typical examples are
2-cyclopentylethyl, cyclohexylmethyl, cyclopentylmethyl,
3-cyclohexyl-n-propyl, and 5-cyclobutyl-n-pentyl.
The term "cycloalkenyl" as employed herein, by itself or as part of
another group, refers to cycloalkenyl groups containing 3 to 9
carbon atoms and 1 to 3 carbon-carbon double bonds. Typical
examples include cyclopropenyl, cyclobutenyl, cyclopentenyl,
cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl,
cyclooctenyl, cyclooctadienyl, cyclooctatrienyl, cyclononenyl, and
cyclononadienyl.
The term "halogen" or "halo" as employed herein by itself or as
part of another group refers to chlorine, bromine, fluorine or
iodine.
The term "monoalkylamine" or "monoalkylamino" as employed herein by
itself or as part of another group refers to the group NH.sub.2
wherein one hydrogen has been replaced by an alkyl group, as
defined above.
The term "dialkylamine" or "dialkylamino" as employed herein by
itself or as part of another group refers to the group NH.sub.2
wherein both hydrogens have been replaced by alkyl groups, as
defined above.
The term "hydroxyalkyl" as employed herein refers to any of the
above alkyl groups wherein one or more hydrogens thereof are
substituted by one or more hydroxyl moieties.
The term "haloalkyl" as employed herein refers to any of the above
alkyl groups wherein one or more hydrogens thereof are substituted
by one or more halo moieties. Typical examples include
fluoromethyl, difluoromethyl, trifluoromethyl, trichloroethyl,
trifluoroethyl, fluoropropyl, and bromobutyl.
The term "carboxyalkyl" as employed herein refers to any of the
above alkyl groups wherein one or more hydrogens thereof are
substituted by one or more carboxylic acid moieties.
The term "heteroatom" is used herein to mean an oxygen atom ("O"),
a sulfur atom ("S") or a nitrogen atom ("N"). It will be recognized
that when the heteroatom is nitrogen, it may form an
NR.sup.aR.sup.b moiety, wherein R.sup.a and R.sup.b are,
independently from one another, hydrogen or C.sub.1 to C.sub.8
alkyl, or together with the nitrogen to which they are bound form a
saturated or unsaturated 5-, 6-, or 7-membered ring.
The phrase "optionally substituted" when not explicitly defined
refers to a group or groups being optionally substituted with one
or more substituents independently selected from the group
consisting of hydroxy, nitro, trifluoromethyl, halogen, C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, C.sub.1-6
alkylenedioxy, C.sub.1-6 aminoalkyl, C.sub.1-6 hydroxyalkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.6-10 aryl, phenoxy,
benzyloxy, 5 10 membered heteroaryl, C.sub.1-6 aminoalkoxy, amino,
mono(C.sub.1-4)alkylamino, di(C.sub.1-4)alkylamino, C.sub.2-6
alkylcarbonylamino, C.sub.2-6 alkoxycarbonylamino, C.sub.2-6
alkoxycarbonyl, C.sub.2-6 alkoxycarbonylalkyl, carboxy, C.sub.2-6
hydroxyalkoxy, (C.sub.1-6)alkoxy(C.sub.2-6)alkoxy,
mono(C.sub.1-4)alkylamino(C.sub.2-6)alkoxy,
di(C.sub.1-4)alkylamino(C.sub.2-6)alkoxy C.sub.2-10
mono(carboxyalkyl)amino, bis(C.sub.2-10 carboxyalkyl)amino,
C.sub.2-6 carboxyalkoxy, C.sub.2-6 carboxyalkyl, carboxyalkylamino,
guanidinoalkyl, hydroxyguanidinoalkyl, cyano, trifluoromethoxy, or
perfluoroethoxy.
Preferred optional substituents include one or more substituents
independently selected from the group consisting of nitro, hydroxy,
carboxy, C.sub.1-4 alkoxy, C.sub.1-4 alkyl, halo, C.sub.1-4
haloalkyl, C.sub.1-4 alkylthio, thio, amino,
mono(C.sub.1-4)alkylamino, and di(C.sub.1-4)alkylamino.
"mdm2" is used herein to mean the murine double minute 2 gene, and
homologous genes found in other animals.
"MDM2" is used herein to mean a protein obtained as a, result of
expression of the mdm2 oncogene. Within the meaning of this term,
it will be understood that MDM2 encompasses all proteins encoded by
mdm2, mutants thereof, alternative splice proteins thereof, and
phosphorylated proteins thereof. Additionally, as used herein, it
will be understood that the term "MDM2" includes MDM2 homologues of
other animals (e.g., HDM2).
"hdm2" is used herein to mean the human gene which is homologous to
the mouse mdm2.
"HDM2" is used herein to mean a protein obtained as a result of
expression of the hdm2 oncogene. Within the meaning of this term,
it will be understood that HDM2 encompasses all proteins encoded by
the hdm2, mutants thereof, alternative splice proteins thereof, and
phosphorylated proteins thereof.
The phrase "antineoplastic agent" is used herein to mean any agent
that is used to treat or prevent cancer or other conditions
comprising uncontrolled proliferation and growth of cells.
Antineoplastic agents include anticancer agents.
The phrase "contacting one or more proteins" is used herein to mean
placing a compound of the present invention in a solution with one
or more proteins of interest. A compound of Formula I and one or
more proteins of interest may be in solution together in an aqueous
solution, non-aqueous solution, or combination of an aqueous
solution and non-aqueous solution. Other proteins may be present in
solution along with the compound of Formula I and the protein of
interest. Other inorganic or organic molecules may be present in
the solution. Such inorganic and organic molecules include, but are
not limited to, NaCl, HEPES, and octyl glucoside. The solution may
be within an animal cell or outside of an animal cell.
The phrase "inhibiting the binding" is used herein to mean
preventing or reducing the direct or indirect association of one or
more molecules, peptides, proteins, enzymes, or receptors; or
preventing or reducing the normal activity of one or more
molecules, peptides, proteins, enzymes, or receptors.
The phrase "inducing apoptosis" is used herein to mean causing
directly or indirectly a cell of animal origin to undergo
apoptosis, a process of controlled, or programmed, cellular
death.
The phrase "HDM2 inhibitor" is used herein to describe an agent
which inhibits the function of HDM2 in the assay described in
Example 217.
The pharmaceutically-acceptable salts of the compounds of Formula I
(in the form of water- or oil-soluble or dispersible products)
include the conventional non-toxic salts or the quaternary ammonium
salts which are formed, e.g., from inorganic or organic acids or
bases. Examples of such acid addition salts include acetate,
adipate, alginate, aspartate, benzoate, benzenesulfonate,
bisulfate, butyrate, citrate, camphorate, camphorsulfonate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate,
hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate,
picrate, pivalate, propionate, succinate, sulfate, tartrate,
thiocyanate, tosylate, and undecanoate. Base salts include ammonium
salts, alkali metal salts such as sodium and potassium salts,
alkaline earth metal salts such as calcium and magnesium salts,
salts with organic bases such as dicyclohexylamine salts,
N-methyl-D-glucamine, and salts with amino acids such as arginine,
lysine, and so forth. Also, the basic nitrogen-containing groups
may be quaternized with such agents as lower alkyl halides, such as
methyl, ethyl, propyl and butyl chlorides, bromides and iodides;
dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl
sulfates; long chain halides such as decyl, lauryl, myristyl and
stearyl chlorides, bromides and iodides; and aralkyl halides like
benzyl and phenethyl bromides and others. Preferred acids for
forming acid addition salts include HCl, acetic acid,
trifluoroacetic acid and fumaric acid.
Compositions and Methods of Use
Compositions of the present invention include pharmaceutical
compositions comprising a compound of Formula I, wherein R.sup.1
R.sup.10 are defined above, and one or more pharmaceutically
acceptable excipients. Preferred compositions of the present
invention are pharmaceutical compositions comprising a compound
selected from a preferred group of compounds of Formula I as
defined above, and one or more pharmaceutically acceptable
excipients.
The pharmaceutical compositions of the invention can be
administered to any animal that can experience the beneficial
effects of the compounds of the invention. Foremost among such
animals are humans, although the invention is not intended to be so
limited.
The pharmaceutical compositions of the present invention can be
administered by any means that achieve their intended purpose. For
example, administration can be by subcutaneous, intravenous,
intramuscular, intraperitoneal, buccal, or ocular routes, rectally,
parenterally, intrasystemically, intravaginally, topically (as by
powders, ointments, drops or transdermal patch), or as an oral or
nasal spray. Alternatively, or concurrently, administration can be
by the oral route. The dosage administered will be dependent upon
the age, health, and weight of the recipient, kind of concurrent
treatment, if any, frequency of treatment, and the nature of the
effect desired.
In addition to the pharmacologically active compounds, the new
pharmaceutical preparations can contain suitable pharmaceutically
acceptable carriers comprising excipients and auxiliaries that
facilitate processing of the active compounds into preparations
that can be used pharmaceutically.
The pharmaceutical preparations of the present invention are
manufactured in a manner that is, itself, known, for example, by
means of conventional mixing, granulating, dragee-making,
dissolving, or lyophilizing processes. Thus, pharmaceutical
preparations for oral use can be obtained by combining the active
compounds with solid excipients, optionally grinding the resulting
mixture and processing the mixture of granules, after adding
suitable auxiliaries, if desired or necessary, to obtain tablets or
dragee cores.
Suitable excipients are, in particular, fillers such as
saccharides, for example, lactose or sucrose, mannitol or sorbitol,
cellulose preparations and/or calcium phosphates, for example,
tricalcium phosphate or calcium hydrogen phosphate, as well as
binders, such as, starch paste, using, for example, maize starch,
wheat starch, rice starch, potato starch, gelatin, tragacanth,
methyl cellulose, hydroxypropyl methylcellulose, sodium
carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired,
disintegrating agents can be added, such as, the above-mentioned
starches and also carboxymethyl-starch, cross-linked polyvinyl
pyrrolidone, agar, or alginic acid or a salt thereof, such as,
sodium alginate. Auxiliaries are, above all, flow-regulating agents
and lubricants, for example, silica, talc, stearic acid or salts
thereof, such as, magnesium stearate or calcium stearate, and/or
polyethylene glycol. Dragee cores are provided with suitable
coatings that, if desired, are resistant to gastric juices. For
this purpose, concentrated saccharide solutions can be used, which
can contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene
glycol, and/or titanium dioxide, lacquer solutions and suitable
organic solvents or solvent mixtures. In order to produce coatings
resistant to gastric juices, solutions of suitable cellulose
preparations, such as, acetylcellulose phthalate or
hydroxypropylmethyl-cellulose phthalate, are used. Dye stuffs or
pigments can be added to the tablets or dragee coatings, for
example, for identification or in order to characterize
combinations of active compound doses.
Other pharmaceutical preparations which can be used orally include
push-fit capsules made of gelatin, as well as soft, sealed capsules
made of gelatin and a plasticizer, such as, glycerol or sorbitol.
The push-fit capsules can contain the active compounds in the form
of granules that may be mixed with fillers such as lactose, binders
such as starches, and/or lubricants such as talc or magnesium
stearate and, optionally, stabilizers. In soft capsules, the active
compounds are preferably dissolved or suspended in suitable
liquids, such as, fatty oils or liquid paraffin. In addition,
stabilizers may be added.
Suitable formulations for parenteral administration include aqueous
solutions of the active compounds in water-soluble form, for
example, water-soluble salts, alkaline solutions and cyclodextrin
inclusion complexes. Especially preferred alkaline salts are
ammonium salts prepared, for example, with Tris, choline hydroxide,
Bis-Tris propane, N-methylglucamine, or arginine. One or more
modified or unmodified cyclodextrins can be employed to stabilize
and increase the water solubility of compounds of the present
invention. Useful cyclodextrins for this purpose are disclosed in
U.S. Pat. Nos. 4,727,064, 4,764,604, and 5,024,998.
In addition, suspensions of the active compounds as appropriate
oily injection suspensions can be administered. Suitable lipophilic
solvents or vehicles include fatty oils, for example, sesame oil,
or synthetic fatty acid esters, for example, ethyl oleate or
triglycerides or polyethylene glycol-400 (the compounds are soluble
in PEG-400). Aqueous injection suspensions can contain substances
that increase the viscosity of the suspension, for example, sodium
carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, the
suspension may also contain stabilizers.
Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, and elixirs. In addition to the active compounds, the
liquid dosage forms may contain inert diluents commonly used in the
art such as, for example, water or other solvents, solubilizing
agents and emulsifiers such as ethyl alcohol, isopropyl alcohol,
ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor, and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitan, and mixtures
thereof.
Suspensions, in addition to the active compounds, may contain
suspending agents as, for example, ethoxylated isostearyl alcohols,
polyoxyethylene sorbitol and sorbitan esters, microcrystalline
cellulose, aluminum metahydroxide, bentonite, agar-agar, and
tragacanth, and mixtures thereof.
Topical administration includes administration to the skin or
mucosa, including surfaces of the lung and eye. Compositions for
topical administration, including those for inhalation, may be
prepared as a dry powder which may be pressurized or
non-pressurized. In nonpressurized powder compositions, the active
ingredients in finely divided form may be used in admixture with a
larger-sized pharmaceutically acceptable inert carrier comprising
particles having a size, for example, of up to 100 micrometers in
diameter. Suitable inert carriers include sugars such as lactose.
Desirably, at least 95% by weight of the particles of the active
ingredient have an effective particle size in the range of 0.01 to
10 micrometers.
Alternatively, the composition may be pressurized and contain a
compressed gas, such as nitrogen or a liquefied gas propellant. The
liquefied propellant medium and indeed the total composition are
preferably such that the active ingredients do not dissolve therein
to any substantial extent. The pressurized composition may also
contain a surface-active agent. The surface-active agent may be a
liquid or solid non-ionic surface-active agent or may be a solid
anionic surface-active agent. It is preferred to use the solid
anionic surface-active agent in the form of a sodium salt.
A further form of topical administration is to the eye. The
compounds and compositions of the present invention are delivered
in a pharmaceutically acceptable ophthalmic vehicle, such that the
compounds are maintained in contact with the ocular surface for a
sufficient time period to allow the compounds to penetrate the
corneal and internal regions of the eye, as for example the
anterior chamber, posterior chamber, vitreous body, aqueous humor,
vitreous humor, cornea, iris/ciliary, lens, choroid/retina and
sclera. The pharmaceutically acceptable ophthalmic vehicle may, for
example, be an ointment, vegetable oil or an encapsulating
material.
Compositions for rectal or vaginal administration are preferably
suppositories which can be prepared by mixing the compounds of the
present invention with suitable non-irritating excipients or
carriers such as cocoa butter, polyethylene glycol or a suppository
wax which are solid at room temperature but liquid at body
temperature and therefore melt in the rectum or vaginal cavity and
release the drugs.
The compositions of the present invention can also be administered
in the form of liposomes. As is known in the art, liposomes are
generally derived from phospholipids or other lipid substances.
Liposomes are formed by mono- or multi-lamellar hydrated liquid
crystals that are dispersed in an aqueous medium. Any non-toxic,
physiologically acceptable and metabolizable lipid capable of
forming liposomes can be used. The present compositions in liposome
form can contain, in addition to the compounds of the present
invention, stabilizers, preservatives, excipients, and the like.
The preferred lipids are the phospholipids and the phosphatidyl
cholines (lecithins), both natural and synthetic. Methods to form
liposomes are known in the art (see, for example, Prescott, Ed.,
Meth. Cell Biol. 14:33 (1976)).
Compounds of the present invention may be used alone or in
combination with one or more additional antineoplastic agents. When
a compound of the present invention is used along with one or more
additional antineoplastic agents, the compound of the present
invention may be formulated with the other antineoplastic agent or
agents so that a pharmaceutical composition comprising a compound
of Formula I and one or more additional antineoplastic agents is
administered to an animal. Alternatively, the compound of Formula I
can be administered as a separate pharmaceutical composition from
the composition comprising the one or more additional
antineoplastic agents. Antineoplastic agents that may be used in
combination with the compounds of the present invention include
compounds selected from the following compounds and classes of
antineoplastic agents:
1. fluoropyrimidines, such as 5-FU (5-fluorouracil),
Fluorodeoxyuridine, Ftorafur, 5'-deoxyfluorouridine, UFT, and S-1
Capecitabine;
2. pyrimidine nucleosides, such as Deoxycytidine, Cytosine
Arabinoside, Cytarabine, Azacitidine, 5-Azacytosine, Gencitabine,
and 5-Azacytosine-Arabinoside;
3. purines, such as 6-Mercaptopurine, Thioguanine, Azathioprine,
Allopurinol, Cladribine, Fludarabine, Pentostatin, and
2-Chloroadenosine;
4. platinum analogues, such as Cisplatin, Carboplatin, Oxaliplatin,
Tetraplatin, Platinum-DACH, Ormaplatin, and CI-973, JM-216;
5. anthracyclines/anthracenediones, such as Doxorubicin,
Daunorubicin, Epirubicin, Idarubicin, and Mitoxantrone;
6. epipodophyllotoxins, such as Etoposide, and Teniposide;
7. camptothecins, such as Irinotecan, Topotecan, 9-Amino
Camptothecin, 10,11-Methylenedioxy Camptothecin, 9-Nitro
Camptothecin, and TAS 103;
8. hormones and hormonal analogues, such as diethylstilbestrol,
Tamoxifen, Toremefine, Tolmudex, Thymitaq, flutamide,
fluoxymesterone, bicalutamide, Finasteride, estradiol, Trioxifene,
dexamethasone, leuproelin acetate, estramustine, Droloxifene,
medroxyprogesterone, megesterol acetate, aminoglutethimide,
testolactone, testosterone, diethylstilbestrol, and
hydroxyprogesterone;
9. enzymes, proteins and antibodies, such as Asparaginase,
Interleukins, Interferons, Leuprolide, and Pegaspargase;
10. vinca alkaloids, such as Vincristine, Vinblastine, Vinorelbine,
and Vindesine;
11. taxanes, such as Paclitaxel, Taxotere and Docetaxel.
Antineoplastic agents that may be used in combination with
compounds of the invention also include compounds selected from the
following Mechanism-Based Classes:
1. Antihormonals--See classification for Hormones and Hormonal
Analogs above, Anastrozole, Goserelin, and Aminoglutethimide;
2. Antifolates, such as methotrexate, leucovorin, aminopterin,
trimetrexate, Trimethoprim, pyritrexim, pyrimethamine, Edatrexate,
and MDAM;
3. Antimicrotubule Agents, such as Taxanes, Vinca Alkaloids, and
Vinorelbine;
4. Alkylating Agents (Classical and Non-Classical), such as
Nitrogen Mustards (Mechlorethamine, Chlorambucil, Melphalan, Uracil
Mustard), Oxazaphosphorines (Ifosfamide, Cyclophosphamide,
Perfosfamide, Trophosphamide), Alkylsulfonates (Busulfan),
Nitrosoureas (Carmustine, Lomustine, Streptozocin), Thiotepa, and
Dacarbazine;
5. Antimetabolites, such as Purines, pyrimidines and nucleoside
analogs, listed above;
6. Antibiotics, such as Anthracyclines/Anthracenediones, Bleomycin,
Dactinomycin, Mitomycin, Plicamycin, Pentostatin, and
Streptozocin;
7. Topoisomerase Inhibitors, such as Camptothecins (Topo I),
Epipodophyllotoxins, AMSA, VP-16 and Ellipticines (Topo II);
8. Antivirals, such as AZT, acyclovir, penciclovir, famcyclovir,
didehydrodideoxythymidine, dideoxycytidine, -SddC, ganciclovir,
dideoxyinosine, and viral-specific protease inhibitors;
9. Miscellaneous Cytotoxic Agents, such as Hydroxyurea, Mitotane,
Fusion Toxins, PZA, Bryostatin, Retinoids, Butyric Acid and
derivatives, Pentosan, Fumagillin, Mitoxantrone, Bone Marrow Growth
Factors, and Procarbazine.
Compounds of the present invention are useful for the treatment of
uncontrolled proliferation of cells and/or cancer. The compounds of
the present invention may produce beneficial cytostatic and/or
cytotoxic effects. The cytostatic effects include the inhibition of
further cell growth and/or cell division. The cytotoxic effects
include the induction of cell death by mechanisms that include
apoptosis and cellular necrosis. Specifically, the compounds of the
present invention are useful in treating the following cancers:
breast cancer, ovarian cancer, cervical carcinoma, endometrial
carcinoma, choriocarcinoma, soft tissue sarcomas, osteosarcomas,
rhabdomyosarcomas, leiomyomas, leiomyosarcomas, head and neck
cancers, lung and bronchogenic carcinomas, brain tumors,
neuroblastomas, esophogeal cancer, colorectal adenocarcinomas,
bladder cancer, urothelial cancers, leukemia, lymphoma, malignant
melanomas, oral squamous carcinoma, hepatoblastoma, glioblastoma,
astrocytoma, medulloblastoma, Ewing's sarcoma, lipoma, liposarcoma,
malignant fibroblast histoma, malignant Schwannoma, testicular
cancers, thyroid cancers, Wilms' tumor, pancreatic cancers,
colorectal adenocarcinoma, tongue carcinoma, gastric carcinoma, and
nasopharyngeal cancers. Preferably, the present invention is used
to treat the cancers selected from the group consisting of breast
cancer, choriocarcinoma, soft tissue sarcomas, osteosarcomas,
rhabdomyosarcomas, lipoma and liposarcoma. The cancers and diseases
listed above are merely meant to be illustrative and are by no
means meant to be a limiting or exhaustive list.
Additionally, the compounds and compositions described herein are
useful to treat any undesired or detrimental condition that results
from the HDM2 protein or the MDM2 protein inhibiting the function
of p53 or other cellular proteins that induce apoptosis, induce
cellular death, or regulate the cellular cycle.
The compounds of the present invention are also useful at
inhibiting the interaction between p53 and HDMX and/or MDMX. MDMX,
also known as MDM4, is a cellular protein involved in the
regulation of the cell cycle. For example, see Riemenschneider et
al., Cancer Res. 59(24):6091 6 (1999).
The compounds of the present invention are also useful for the
treatment and prevention of inflammatory conditions. The compounds
of the present invention can be administered as anti-inflammatory
agents that reduce the degree of or eliminate inflammation of
tissues.
The compounds of the present invention are also useful for the
treatment of autoimmune diseases and conditions. The compounds of
the present invention can be administered to reduce or eliminate
the symptoms of an autoimmune disease. Autoimmune diseases include
any disease in which an animal's immune system reacts adversely to
a self-antigen. A self-antigen is any antigen that is normally
found in the animal's body. Representative autoimmune diseases
include Hashimoto's thyroiditis, Grave's disease, multiple
sclerosis, pernicious anemia, Addison's disease, insulin-dependent
diabetes mellitus, rheumatoid arthritis, systemic lupus
erythematosus (SLE or lupus), dermatomyositis, Crohn's disease,
Wegener's granulomatosis, Anti-Glomerular Basement Membrane
Disease, Antiphospholipid Syndrome, Dermatitis Herpetiformis,
Allergic Encephalomyelitis, Glomerulonephritis, Membranous
Glomerulonephritis, Goodpasture Syndrome, Lambert-Eaton, Myasthenic
Syndrome, Myasthenia Gravis, Bullous Pemphigoid,
Polyendocrinopathies, Reiter's Disease, and Stiff-Man Syndrome.
Preferably, the present invention is used to treat rheumatoid
arthritis or systemic lupus erythematosus.
Inhibitors of the interaction of HDM2 and/or MDM2 and p53 are also
useful for treating cancer, inhibiting cell growth/replication, and
inducing cellular apoptosis and necrosis, when administered along
with agents that cause or induce DNA damage (see Chen et al. Proc.
Natl. Acad. Sci. USA 95:195 200 (1998)). Compounds of the present
invention may be used to treat cancer, inhibit cell
growth/replication, and induce cellular apoptosis and necrosis, by
administering a compound of the present invention along with agents
that cause or induce DNA damage. Agents that induce DNA damage
include radiation and chemical agents. The radiation can be
administered either internally or externally. Chemical agents
include any compounds or elements that cause or induce damage to
DNA.
The compounds of the present invention may be administered in an
effective amount within the dosage range of about 0.01 mg/kg to
about 300 mg/kg, preferably between 1.0 mg/kg to 100 mg/kg body
weight. Compounds of the present invention may be administered in a
single daily dose, or the total daily dosage may be administered in
divided doses of two, three or four times daily.
Preparation of Compounds
The present invention is also concerned with the syntheses of
substituted 1,4-benzodiazepin-2,5-dione carboxylic acids. The
compounds of the present invention can be prepared utilizing the
modification of Ugi condensation products, according to the
synthetic pathway shown in Scheme 1 or Scheme 2 and as detailed in
Keating and Armstrong, J. Am. Chem. Soc., 118: 2574 2583
(1996).
##STR00003##
##STR00004##
Appropriately substituted or unsubstituted anthranilic acids 1 or
11, amines 3, aldehydes or ketones 2 can be used to prepare the
compounds of the present invention, wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.8, R.sup.9, and R.sup.10
are defined above. The acid compounds of the present invention can
be prepared by optional hydrolysis of ester using a base, such as
NaOH, in an appropriate solvent, such as methanol/water. In Scheme
2, the standard Suzuki (Miyaura, N; Yanagi, T.; Suzuki, A., Synth.
Commun., 11: 513 (1981)) cross coupling condition can be used to
introduce R.sup.2 (from compound 12 to 6). While R.sup.5 is
selected as a group other than hydrogen, R.sup.5 can be introduced
by using R.sup.5Br in the presence of a base, such as NaH, and a
solvent, such as THF, or by using a standard Mitsunobu coupling
procedure (Mitsunobu, O., Synthesis, 1, (1981)) such as diethyl
azodicarboxylate, and triphenylphosphine in THF. Compound 7 can be
converted into compound 8 or 9 by using an appropriate reducing
reagent, such as BH.sub.3.S(Me).sub.2, in a solvent such as THF.
Compound 10 can be made through reaction of compound 7 with
Lawesson's reagent
(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide)
in a solvent such as THF.
The following examples illustrate, but do not limit, the compounds,
methods and compositions of the present invention. Other suitable
modifications and adaptations of the variety of conditions and
parameters normally encountered in clinical therapy and which are
obvious to those skilled in the art are within the spirit and scope
of the invention.
EXAMPLES
The compounds in the examples below were synthesized by the
following general procedures.
General Procedure for the Synthesis of Non-commercially Available
Anthranilic Acids
A solution of the appropriate aniline (50.0 mmol) in acetic acid
(30.0 mL) was heated to 45.degree. C. Bromine (55.5 mmol, 2.8 mL)
was then added dropwise at a rate to keep the temperature between
50 55.degree. C. The temperature was held at 50.degree. C. for 1.5
h. The reaction was allowed to cool to ambient temperature and was
poured into ice with stirring. Sodium bisulfite (1.0 g) was added
and stirred for 30 min. The solution was extracted with ethyl
acetate (2.times.50.0 mL). The combined organic extracts were
washed with saturated sodium bicarbonate, brine, dried over sodium
sulfate, filtered and concentrated in vacuo to give a dark oil. The
oil was purified by flash chromatography (silica gel, 5 10% ethyl
acetate in hexanes) to give the aryl bromide as a light brown
oil.
A solution of the aryl bromide (12.0 mmol) in N,N-dimethylformamide
(8.0 mL) was stirred at ambient temperature. Copper cyanide (15.0
mmol, 1.3 g) was added and the reaction was heated to 155.degree.
C. for 4 h. The reaction was allowed to cool and poured into a
solution of ethylene diamine (0.1 mL) in water (130.0 mL) and
stirred for 30 min. The solution was extracted with ethyl acetate
(2.times.70.0 mL). The organic extracts were combined and washed
with saturated ammonium chloride and brine, dried with sodium
sulfate and concentrated in vacuo. The residue was then purified by
flash chromatography (silica gel, 10% ethyl acetate in hexane) to
give the aryl cyanide as a orange oil.
To a solution of the aryl cyanide (1.5 mmol) in acetic acid (2.0
mL) was added 50% sulfuric acid (6.0 mL), The reaction was heated
to reflux for 2.5 h. The reaction was allowed to cool to ambient
temperature and poured into ice (50.0 g). The solution was
neutralized with potassium hydroxide (6M) and extracted with ethyl
acetate (2.times.40.0 mL). The combined organics were washed with
brine and dried with sodium sulfate, filtered and dried in vacuo to
a solid. The solid was purified by flash chromatography (silica
gel, 15% ethyl acetate in methylene chloride to 8% methanol in
methylene chloride) to give the anthranilic acid as a white
solid.
To a solution of the anthranilic acid (4.2 mmol) in 1,4-dioxane
(20.0 mL) and 10% sodium hydroxide (5.0 mL) was added
di-tertbutyl-dicarbonate (12.0 mmol). The reaction was stirred at
ambient temperature for 3 days. The reaction was then concentrated
in vacuo and poured into water (25.0 mL) and ethyl acetate (50.0
mL). It was then acidified with cold 10% citric acid. The organic
layers were washed with brine and dried with sodium sulfate and
filtered. The organics were concentrated in vacuo to a solid and
triturated with hexane. The solids were filtered, and washed with
hexane and dried under high vacuum to give the title compound as a
white solid.
General Procedure for the Synthesis of Benzodiazepine Compounds
A solution of the aldehyde (0.20 mmol) and amino ester (0.20 mmol)
in methanol (2.0 mL) were shaken at ambient temperature for 30 min.
To this solution was added a solution of cyclohexene-1-isonitrile
(0.21 mmol) in hexanes, followed by the anthranilic acid (0.20
mmol). The solution was then shaken for 3 days at ambient
temperature. The reaction was cooled in a ice bath and acetyl
chloride (0.2 mL) was added slowly. The solution was then shaken
for an additional 3 h and concentrated in vacuo. The residue was
purified using pre-packed silica cartridges (methylene chloride to
10% ethyl acetate in methylene chloride). The pure ester was then
concentrated back down in vacuo, dissolved in methanol (1.5 mL),
and 10% sodium hydroxide (0.15 mL) was added. The reaction mixture
was shaken overnight at ambient temperature. The solution was then
concentrated in vacuo and acidified with hydrochloric acid (1M).
The precipitates were extracted with ethyl acetate, separated and
the organics were concentrated in vacuo. The residue was purified
using pre-packed silica cartridges (8% ethyl acetate in methylene
chloride to 10% methanol in methylene chloride) to give the title
compounds (0.015 0.050 g).
General Procedure for the Alkylation of Benzodiazepine
Compounds
To a solution of the benzodiazepine (0.1 mmol) and alcohol (0.2
mmol) in tetrahydrofuran (1.0 mL) was added triphenylphosphine (0.2
mmol, 0.052 g) in tetrahydrofuran (1.0 mL). The solution was shaken
5 minutes then diisopropyl azodicarboxylate (0.2 mmol, 0.040 mL)
was added, and the mixture was shaken at ambient temperature
overnight. The reaction was concentrated in vacuo. The residue was
purified by preparative plate chromatography (silica gel, 20% ethyl
acetate in methylene chloride, bottom band). The isolated ester was
dissolved in methanol (1 mL) and sodium hydroxide (1M, 0.2 mL) was
added and the reaction mixture was shaken at ambient temperature
overnight. The reaction was concentrated in vacuo, water (0.5 mL)
was added, followed by acidification with hydrochloric acid (1M,
0.3 mL). The resulting precipitate was extracted with ethyl acetate
(1 mL) and separated. The organics were dried in vacuo and the
residues purified using a preparative plate chromatography (silica
gel, 8% methanol in methylene chloride, bottom band) to give the
title compounds (0.012 0.030 g).
General Procedure for the Boronic Acid Cross Coupling of
Benzodiazepine Compounds
Benzodiazepine (0.05 mmol), boronic acid (3 eq, 0.15 mmol), and
Pd(PPh.sub.3).sub.4 (0.04 eq, 0.002 mmol) were placed in a 2 mL
vial equipped with a magnetic stir bar. The vial was fitted with a
rubber septum then evacuated and backflushed with dry N.sub.2.
Tetrahydrofuran (THF, 0.8 mL) and 2M Na.sub.2CO.sub.3 (0.2 mL) were
added to the vial via syringe. The reaction vessel was capped
tightly under a N.sub.2 purge then heated to 50.degree. C. for 12
h. After cooling to ambient temperature, the solvent was removed
under reduced pressure. The residue was then purified by Sep-Pak
(10 g silica gel, methylene chloride to 10% ethyl acetate in
methylene chloride) to give the title compound.
General Procedure for the Reduction of 1,4-benzodiazepines
1) The benzodiazepine ester (0.070 mmol) was placed in a 4 mL vial
equipped with a magnetic stir bar. The vial was fitted with a
rubber septum then evacuated and backflushed with N.sub.2.
Borane-dimethylsulfide (4 eq., 0.28 mmol, 0.14 mL of 2M THF
solution) was added via syringe. The reaction was stirred at
ambient temperature for 15 hours. The solvent was removed under
reduced pressure then the residue was dissolved in ethyl acetate.
The organic phase was washed with 1M NaOH then the aqueous phase
was extracted twice with ethyl acetate. The combined organic phase
was dried over anhydrous magnesium sulfate, filtered, and the
solvent removed under reduced pressure. The mono- and di-reduced
products were separated by column chromatography on silica gel,
eluting with 10% ethyl acetate in hexanes to give the title
compound.
2) The benzodiazepine acid (0.023 mmol) was placed in a 4 mL vial
equipped with a magnetic stir bar. The vial was fitted with a
rubber septum then evacuated and backflushed with N.sub.2. Dry THF
(1 mL) and borane-dimethylsulfide (4 eq., 0.093 mmol, 46 .mu.L of
2M THF solution) were successively added via syringe and
microsyringe, respectively. The reaction was stirred at ambient
temperature for 16 hours then additional borane-dimethylsulfide (8
eq., 0.186 mmol, 92 .mu.L of 2M THF solution) was added to the
reaction. The reaction was stirred at ambient temperature for an
additional 4 hours then the solvent was removed under reduced
pressure. The residue was purified by column chromatography using a
5 g silica gel SEP-pak column, eluting with 20% ethyl acetate in
dichloromethane. The amide reduction products were further
separated by preparative TLC on a 1000 micron silica gel plate,
developed with 20% ethyl acetate in hexanes to give the title
compound.
General Procedure for the Preparation of 1,4-benzodiazepine
Amides
The 1,4-benzodiazepine carboxylic acid (0.057 mmol) and EDC (1.5
eq., 0.086 mmol, 16.5 mg) were placed in a 4 mL vial equipped with
a magnetic stir bar. The vial was fitted with a rubber septum, then
evacuated and backflushed with dry N.sub.2. Dry dichloromethane (2
mL) was added via syringe. Once the solids dissolved, the amine
(1.5 eq, 0.086 mmol) and triethylamine (2.5 eq., 0.143 mmol, 20
.mu.L) were successively added via microsyringe. The reaction was
stirred at ambient temperature for 2 hours then the volatiles were
removed under reduced pressure. The crude product was purified by
column chromatography using a 5 g silica gel SEP-pak column eluting
with 50% ethyl acetate in dichloromethane.
Example 1
[7-Iodo-2,5-dioxo-3-(4-trifluoromethylphenyl)-1,2,3,5-tetrahydro-benzo[e][-
1,4]diazepin-4-yl]phenylacetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.68 (s, 0.4H), 10.52
(s, 0.6H), 7.79 (s, 0.4H), 7.72 (s, 0.6H), 7.52 7.22 (m, 9H), 7.00
(m, 1H), 6.63 (d, J=8.4 Hz, 0.4H), 6.53 (d, J=8.4 Hz, 0.6H) 6.36
(s, 1H), 5.96 (s, 0.6H), 5.28 (s, 0.4H). Mass spectrum (LCMS, ESI
pos) Calcd. for C.sub.24H.sub.16F.sub.3N.sub.2O.sub.4I: 580.0;
Found: 580.9(M+H).
Example 2
[3-(4-Chlorophenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diaze-
pin-4-yl]phenylacetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.74 (s, 0.6H), 10.56
(s, 0.4H), 7.78 6.89 (m, 11H), 6.64 (d, J=8.7 Hz, 0.6H), 6.56 (d,
J=8.7 Hz, 0.4H), 6.30 (br s, 1H), 5.65 (s, 0.4H), 5.14 (s, 0.6H).
Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.23H.sub.16N.sub.2O.sub.4ICI: 546.0; Found: 546.8(M+H).
Example 3
[3-(4-ethyl-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diaze-
pin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.57 (s, 0.5H), 10.40
(s, 0.5H), 7.78 6.54 (m, 12H), 6.35 (s, 0.5H), 6.31 (s, 0.5H),
5.89(s, 0.5H), 5.18 (s, 0.5H), 2.38 (m, 2H), 1.00 (m, 3H). Mass
spectrum (LCMS, ESI pos) Calcd. for
C.sub.25H.sub.21N.sub.2O.sub.4I: 540.1; Found: 540.8(M+H).
Example 4
[7-Iodo-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro-benzo[e-
][1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.77 (s, 0.6H), 10.55
(s, 0.4H), 7.69 6.99 (m, 11H), 6.63 (d, J=8.6 Hz, 0.6H), 6.55 (d,
J=8.6 Hz, 0.4H), 6.31 (br s, 1H), 5.63 (s, 0.4H), 5.18 (s, 0.6H).
Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.24H.sub.16F.sub.3N.sub.2O.sub.5I: 596.0; Found:
596.8(M+H).
Example 5
[7-Iodo-3-(4-isopropyl-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]d-
iazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.58 (s, 0.6H), 10.40
(s, 0.4H), 7.63 6.54 (m, 12H), 6.30 (br s, 1H), 5.64(s, 0.4H), 5.08
(s, 0.6H), 2.60 (m, 1H), 0.96 (m, 6H). Mass spectrum (LCMS, ESI
pos) Calcd. for C.sub.26H.sub.23N.sub.2O.sub.4I: 554.1; Found:
554.9(M+H).
Example 6
[2,5-Dioxo-3-(4-trifluoromethyl-phenyl)-1,2,3,5-tetrahydro-benzo[e][1,4]di-
azepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.70 (s, 0.6H), 10.2
(s, 0.4H), 7.7 6.9 (m, 13H), 6.42 (s, 0.4H), 6.39 (s, 0.6H), 5.86
(s, 0.4H), 5.30 (s, 0.6H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.24H.sub.17F.sub.3N.sub.2O.sub.4: 454.1; Found:
455.0(M+H).
Example 7
2-[7-Iodo-2,5-dioxo-3-(4-trifluoromethyl-phenyl)-1,2,3,5-tetrahydro-benzo[-
e][1,4]diazepin-4-yl]-3-phenyl-propionic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.81 (s, 0.6H), 10.56
(s, 0.4H), 7.70 7.10 (m, 11H), 6.55 (m, 1H), 5.79 (s, 0.6H), 5.59
(br s, 0.6H), 5.51 (s, 0.4H), 5.31 (br s, 0.4H), 3.35 (m, 2H). Mass
spectrum (LCMS, ESI pos) Calcd. for
C.sub.25H.sub.18F.sub.3N.sub.2O.sub.4I: 594.0; Found:
595.0(M+H).
Example 8
(7-Iodo-2,5-dioxo-3-phenyl-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)--
phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.69 (s, 0.6H), 10.47
(s, 0.4H), 7.78 6.79 (m, 12H), 6.63 (d, J=8.3 Hz, 0.6H), 6.54 (d,
J=8.3 Hz, 0.4H), 6.38 (s, 0.6H), 6.34 (s, 0.4H), 5.83 (s, 0.4H),
5.23 (s, 0.6H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.23H.sub.17N.sub.2O.sub.4I: 512.0; Found: 513.0(M+H).
Example 9
[7-Iodo-2,5-dioxo-3-(3-trifluoromethyl-phenyl)-1,2,3,5-tetrahydro-benzo[e]-
[1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.76 (s, 0.6H), 10.53
(s, 0.4H), 7.81 6.90 (m, 11H), 6.61 (d, J=8.7 Hz, 0.6H), 6.54 (d,
J=8.6 Hz, 0.4H), 6.40 (s, 0.6H), 6.36 (s, 0.4H), 5.78 (s, 0.4H),
5.40 (s, 0.6H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.24H.sub.16F.sub.3N.sub.2O.sub.4I: 580.0; Found:
580.8(M+H).
Example 10
(7-Iodo-2,5-dioxo-3-p-tolyl-1,2,3,5-tetrahydrobenzo[e][1,4]diazepin-4-yl)--
phenylacetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.64 (s, 0.6H), 10.45
(s, 0.4H), 7.78 6.54 (m, 11H), 6.37 (s, 0.6H), 6.30 (s, 0.4H), 5.77
(s, 0.4H), 5.16 (s, 0.6H), 5.12 (s, 1H), 2.05 (s, 3H). Mass
spectrum (LCMS, ESI pos) Calcd. for
C.sub.24H.sub.19N.sub.2O.sub.4I: 526.0; Found: 526.8(M+H).
Example 11
[7-Iodo-3-(4-methoxy-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]dia-
zepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.64 (s, 0.6H), 10.44
(s, 0.4H), 7.78 6.54 (m, 12H), 6.37 (s, 0.6H), 6.30 (s, 0.4H), 5.72
(s, 0.4H), 5.16 (s, 0.6H), 3.61 (s, 1H), 3.55 (s, 2H). Mass
spectrum (LCMS, ESI pos) Calcd. for
C.sub.24H.sub.19N.sub.2O.sub.5I: 542.0; Found: 542.8(M+H).
Example 12
(7-Iodo-3-naphthalen-2-yl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazep-
in-4-yl)-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.83 (s, 0.75H),
10.72 (s, 0.25H), 8.01 7.00 (m, 14H), 6.62 (d, J=8.3 Hz, 0.75H),
6.57 (d, J=8.3 Hz, 0.25H), 6.44 (s, 0.75H), 6.21 (s, 0.25H), 5.52
(s, 0.25H), 5.26 (s, 0.75H). Mass spectrum (LCMS, ESI pos) Calcd.
for C.sub.27H.sub.19N.sub.2O.sub.4I: 562.0; Found: 562.9(M+H).
Example 13
[3-(4-tert-Butyl-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]-
diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.61 (s, 0.6H), 10.41
(s, 0.4H), 7.78 6.54 (m, 12H), 6.32 (s, 0.6H), 6.27 (s, 0.4H),
5.76(s, 0.4H), 5.13 (s, 0.6H), 1.12(s, 3H), 1.07 (s, 6H). Mass
spectrum (LCMS, ESI pos) Calcd. for
C.sub.27H.sub.25N.sub.2O.sub.4I: 568.1; Found: 568.9(M+H).
Example 14
[3-(2-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diaz-
epin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.66 (s, 0.4H), 10.53
(s, 0.6H), 7.81 6.90 (m, 11H), 6.72 (s, 0.4H), 6.61 (d, J=8.7 Hz,
0.4H), 6.54 (d, J=8.6 Hz, 0.6H), 6.36 (s, 0.6H), 5.22 (s, 0.6H),
5.12 (s, 0.4H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.23H.sub.16N.sub.2O.sub.4ICl: 546.0; Found: 547.8(M+H).
Example 15
[3-(3-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diaz-
epin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.74 (s, 0.6H), 10.53
(s, 0.4H), 7.79 6.76 (m, 11H), 6.65 (d, J=8.7 Hz, 0.6H), 6.56 (d,
J=8.6 Hz, 0.4H), 6.34 (s, 0.6H), 6.31 (s, 0.4H), 5.72 (s, 0.4H),
5.25 (s, 0.6H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.23H.sub.16N.sub.2O.sub.4I: 546.0; Found: 546.9(M+H).
Example 16
[3-(4-Benzyloxy-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]d-
iazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.66 (s, 0.7H), 10.47
(s, 0.3H), 7.78 6.56 (m, 17H), 6.35 (s, 0.7H), 6.28 (s, 0.3H), 5.66
(s, 0.3H), 5.13 (s, 0.7H), 4.95 (s, 0.5H), 4.89 (s, 1.5H). Mass
spectrum (LCMS, ESI pos) Calcd. for
C.sub.30H.sub.23N.sub.2O.sub.5I: 618.1; Found: 618.8(M+H).
Example 17
[7-Iodo-2,5-dioxo-3-(4-phenoxy-phenyl)-1,2,3,5-tetrahydro-benzo[e][1,4]dia-
zepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.61 (s, 0.5H), 10.41
(s, 0.5H), 7.80 6.55 (m, 17H), 6.33 (s, 0.5H), 5.88 (s, 0.5H), 5.36
(s, 0.5H), 5.22 (s, 0.5H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.29H.sub.21N.sub.2O.sub.5I: 604.0; Found: 604.8(M+H).
Example 18
[7-Iodo-2,5-dioxo-3-(2-trifluoromethyl-phenyl)-1,2,3,5-tetrahydro-benzo[e]-
[1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.72 (s, 0.5H), 10.61
(s, 0.5H), 7.81 6.54 (m, 12H), 6.40 (s, 0.5H), 5.35 (s, 0.5H), 5.29
(s, 0.5H), 5.08 (s, 0.5H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.24H.sub.16F.sub.3N.sub.2O.sub.4I: 580.0; Found:
580.9(M+H).
Example 19
3-(3,4-Dichloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]d-
iazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.79 (s, 0.8H), 10.58
(s, 0.2H), 7.81 6.84 (m, 10H), 6.67 (d, J=8.5 Hz, 0.8H), 6.58 (d,
J=8.5 Hz, 0.2H), 6.33 (s, 0.8H), 6.31 (s, 0.2H), 5.35 (s, 0.2H),
5.24 (s, 0.8H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.23H.sub.15N.sub.2O.sub.4ICl.sub.2: 579.9; Found:
580.8(M+H).
Example 20
[3-(3,4-Dimethoxy-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4-
]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.64 (s, 0.5H), 10.41
(s, 0.5H), 7.81 7.22 (m, 10H), 6.67 (d, J=8.4 Hz, 0.5H), 6.55 (d,
J=8.5 Hz, 0.5H), 6.42 (s, 0.5H), 6.12 (s, 0.5H), 5.62 (s, 0.5H)
5.30 (s, 0.5H), 3.54 (s, 3H), 3.43 (s, 3H). Mass spectrum (LCMS,
ESI pos) Calcd. for C.sub.25H.sub.21N.sub.2O.sub.6I: 572.0; Found:
572.8(M+H).
Example 21
[3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-
-benzo[e][1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.65 (s, 0.7H), 10.46
(s, 0.3H), 7.78 6.47 (m, 11H), 6.32 (s, 0.8H), 6.25 (s, 0.8H), 6.23
(s, 0.2H), 5.10 (s, 0.2H), 4.07 (br s, 4H). Mass spectrum (LCMS,
ESI pos) Calcd. for C.sub.25H.sub.19N.sub.2O.sub.6I: 570.; Found:
570.90 (M+H).
Example 22
[3-(4-Bromo-2-fluoro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][-
1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.74 (s, 0.6H), 10.47
(s, 0.4H), 7.81 7.01 (m, 10H), 6.67 (d, J=8.7 Hz, 0.6H), 6.58 (d,
J=8.6 Hz, 0.4H), 6.26 (s, 0.4H), 6.13 (s, 0.6H) 5.77 (s, 0.4H),
5.14 (s, 0.6H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.23H.sub.15N.sub.2O.sub.4IBrF: 607.9; Found: 608.8(M+H).
Example 23
[3-(2-Fluoro-4-trifluoromethyl-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-
-benzo[e][1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.76 (s, 0.8H), 10.47
(s, 0.2H), 7.81 6.81 (m, 10H), 6.66 (d, J=8.4 Hz, 0.8H), 6.56 (d,
J=8.4 Hz, 0.2H), 6.31 (s, 0.2H), 6.16 (s, 0.8H) 6.02 (s, 0.2H),
5.29 (s, 0.8H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.24H.sub.15N.sub.2O.sub.4IF.sub.4: 598.0; Found:
598.9(M+H).
Example 24
[3-(3-Fluoro-4-trifluoromethyl-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-
-benzo[e][1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.82 (s, 0.8H), 10.61
(s, 0.2H), 7.81 6.90 (m, 10H), 6.65 (d, J=8.5 Hz, 0.8H), 6.58 (d,
J=8.5 Hz, 0.2H), 6.31 (s, 0.2H), 6.29 (s, 0.8H) 5.74 (s, 0.2H),
5.29 (s, 0.8H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.24H.sub.15N.sub.2O.sub.4IF.sub.4: 598.0; Found:
598.9(M+H).
Example 25
[3-(4-Chloro-3-fluoro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e]-
[1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.75 (s, 0.8H), 10.57
(s, 0.2H), 7.81 6.60 (m, 11H), 6.27 (bs, 1H), 5.67 (s, 0.2H), 5.22
(s, 0.8H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.23H.sub.15N.sub.2O.sub.4IClF: 564.0; Found: 564.9(M+H).
Example 26
[3-(4-Bromo-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diaze-
pin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.76 (s, 0.6H), 10.57
(s, 0.4H), 7.80 6.82 (m, 11H), 6.64 (d, J=8.6 Hz, 0.6H), 6.54 (d,
J=8.6 Hz, 0.4H), 6.32 (s, 0.6H), 6.27 (s, 0.4H) 5.58 (s, 0.4H),
5.10 (s, 0.6H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.23H.sub.16N.sub.2O.sub.4IBr: 589.9; Found: 591.8(M+H).
Example 27
[8-Chloro-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]di-
azepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.78 (s, 0.8H), 10.58
(s, 0.2H), 7.53 6.83 (m, 12H), 6.34 (s, 0.8H), 6.30 (s, 0.2H), 5.66
(s, 0.2H), 5.14 (s, 0.8H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.23H.sub.16N.sub.2O.sub.4Cl.sub.2: 454.0; Found:
454.9(M+H).
Example 28
[7-Chloro-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]di-
azepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.79 (s, 0.7H), 10.58
(s, 0.3H), 7.50 6.77 (m, 12H), 6.34 (s, 0.7H), 6.31 (s, 0.3H), 5.69
(s, 0.3H), 5.15 (s, 0.7H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.23H.sub.16N.sub.2O.sub.4ICl.sub.2: 454.0; Found:
454.9(M+H).
Example 29
[7-Bromo-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]dia-
zepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.81 (s, 0.7H), 10.61
(s, 0.3H), 7.59 6.92 (m, 11H), 6.80 (d, J=8.6 Hz, 0.7H), 6.72 (d,
J=8.6 Hz, 0.3H), 6.33 (s, 0.7H), 6.29 (s, 0.3H) 5.60 (s, 0.3H),
5.13 (s, 0.7H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.23H.sub.16N.sub.2O.sub.4ClBr: 498.0; Found: 499.1(M+H).
Example 30
[3-(4-Chloro-phenyl)-7-methoxy-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]d-
iazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.52 (s, 0.7H), 10.33
(s, 0.3H), 7.50 6.81 (m, 11H), 6.75 (d, J=8.9 Hz, 0.7H), 6.68 (d,
J=8.9 Hz, 0.3H), 6.32 (s, 0.7H), 6.29 (s, 0.3H) 5.47 (s, 0.3H),
5.11 (s, 0.7H), 3.64 (s, 3H). Mass spectrum (LCMS, ESI pos) Calcd.
for C.sub.24H.sub.19N.sub.2O.sub.5Cl: 450.1; Found: 450.9(M+H).
Example 31
[3-(4-Chloro-phenyl)-7-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]di-
azepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.59 (s, 0.6H), 10.39
(s, 0.4H), 7.50 6.85 (m, 11H), 6.72 (d, J=8.1 Hz, 0.7H), 6.65 (d,
J=8.1 Hz, 0.3H), 6.33 (s, 0.7H), 6.29 (s, 0.3H) 5.55 (s, 0.3H),
5.14 (s, 0.7H), 2.14 (s, 2H), 2.13 (s, 1H). Mass spectrum (LCMS,
ESI pos) Calcd. for C.sub.24H.sub.19N.sub.2O.sub.4Cl: 434.1; Found:
435.0(M+H).
Example 32
[3-(4-Chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-naphtho[2,3-e][1,4]diaze-
pin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.87 (s, 0.6H), 10.71
(s, 0.4H), 8.21 6.98 (m, 12H), 6.38 (s, 0.6H), 6.32 (s, 0.4H) 5.52
(s, 0.4H), 5.20 (s, 0.6H) 2.14 (s, 2H) 2.13 (s, 1H). Mass spectrum
(LCMS, ESI pos) Calcd. for C.sub.27H.sub.19N.sub.2O.sub.4Cl: 470.1;
Found: 471.0(M+H).
Example 33
[8-Chloro-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro-benzo-
[e][1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.76 (s, 0.9H), 10.55
(s, 0.1H), 7.53 6.80 (m, 12H), 6.32 (s, 1H), 5.18 (s, 1H). Mass
spectrum (LCMS, ESI pos) Calcd. for
C.sub.24H.sub.16N.sub.2O.sub.5Cl.sub.2F.sub.3: 504.1; Found:
505.0(M+H).
Example 34
[7-Chloro-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro-benzo-
[e][1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.81 (s, 0.5H), 10.59
(s, 0.5H), 7.50 7.00 (m, 11H), 6.85 (d, J=8.8 Hz, 0.5H), 6.77 (d,
J=8.8 Hz, 0.5H), 6.32 (s, 1H), 5.67 (s, 0.5H), 5.18 (s, 0.5H). Mass
spectrum (LCMS, ESI pos) Calcd. for
C.sub.24H.sub.16N.sub.2O.sub.5ClF.sub.3: 504.1; Found:
504.9(M+H).
Example 35
[7-Bromo-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro-benzo[-
e][1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.78 (s, 0.9H), 10.56
(s, 0.1H), 7.58 6.98 (m, 11H), 6.79 (d, J=8.5 Hz, 0.9H), 6.70 (d,
J=8.5 Hz, 0.1H), 6.33 (s, 1H), 5.75 (s, 0.1H), 5.20 (s, 0.9H). Mass
spectrum (LCMS, ESI pos) Calcd. for
C.sub.24H.sub.16N.sub.2O.sub.5BrF.sub.3: 548.0; Found:
548.8(M+H).
Example 36
[7-Methoxy-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro-benz-
o[e][1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.52 (s, 0.6H), 10.30
(s, 0.4H), 7.52 6.79 (m, 11H), 6.74 (d, J=8.8 Hz, 0.6H), 6.66 (d,
J=8.8 Hz, 0.4H), 6.33 (s, 0.4H), 6.30 (s, 0.6H) 5.56 (s, 0.4H),
5.16 (s, 0.6H), 3.62 (s, 3H). Mass spectrum (LCMS, ESI pos) Calcd.
for C.sub.25H.sub.19N.sub.2O.sub.6F.sub.3: 500.1; Found:
500.9(M+H).
Example 37
[7-Methyl-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro-benzo-
[e][1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.60 (s, 0.6H), 10.41
(s, 0.4H), 7.51 7.00 (m, 11H), 6.71 (d, J=8.2 Hz, 0.6H), 6.64 (d,
J=8.2 Hz, 0.4H), 6.30 (s, 1H), 5.51 (s, 0.4H), 5.16 (s, 0.6H), 2.11
(s, 2H), 2.10 (s, 1H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.25H.sub.19N.sub.2O.sub.5F.sub.3: 484.1; Found:
485.0(M+H).
Example 38
[2,5-Dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro-naphtho[2,3-e]-
[1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.86 (s, 0.8H), 10.51
(s, 0.2H), 7.72 6.90 (m, 15H), 6.37 (s, 1H), 5.57 (s, 0.4H), 5.25
(s, 0.6H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.28H.sub.19N.sub.2O.sub.5F.sub.3: 520.1; Found:
521.0(M+H).
Example 39
2-[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]di-
azepin-4-yl]-3-phenyl-propionic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.76 (s, 0.6H), 10.51
(s, 0.4H), 7.72 6.95 (m, 11H), 6.57 (d, J=8.9 Hz, 0.4H), 6.54 (d,
J=8.9 Hz, 0.6H), 5.57 (br s, 1H), 5.39 (s, 0.6H) 5.28 (s, 0.4H),
3.41 (d, J=4.2 Hz, 0.8H), 3.37 (d, J=4.2 Hz, 1.2H). Mass spectrum
(LCMS, ESI pos) Calcd. for C.sub.24H.sub.18N.sub.2O.sub.4ICl:
560.0; Found: 560.8(M+H).
Example 40
3-(4-Chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrah-
ydro-benzo[e][1,4]diazepin-4-yl]-propionic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.76 (s, 0.8H), 10.54
(s, 0.2H), 7.72 6.95 (m, 10H), 6.58(d, J=8.4 Hz, 0.2H), 6.54 (d,
J=8.4 Hz, 0.8H), 5.54 (br s, 1.4H), 5.35 (s, 0.2H), 5.13 (s, 0.4H),
3.41 (d, J=4.4 Hz, 0.8H), 3.37 (d, J=4.4 Hz, 1.2H). Mass spectrum
(LCMS, ESI pos) Calcd. for C.sub.24H.sub.17N.sub.2O.sub.4ICl.sub.2:
594.0; Found: 594.8 (M+H).
Example 41
2-[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]di-
azepin-4-yl]-3-(4-hydroxy-phenyl)-propionic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.74 (s, 0.9H), 10.55
(s, 0.1H), 9.16 (s, 0.1H), 9.11 (s, 0.9H), 7.71 (s, 0.2H), 7.62 (d,
J=1.9 Hz, 0.8H), 7.49 (m, 1H), 7.15 6.96 (m, 6H), 6.57(m, 3H), 5.63
(br s, 0.8H), 5.46 (br s, 0.8H), 5.21 (br s, 0.4H), 3.25 (m, 2H).
Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.24H.sub.18N.sub.2O.sub.5ICl: 576.0; Found: 576.8(M+H).
Example 42
2-[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]di-
azepin-4-yl]-3-cyclohexyl-propionic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.96 (s, 0.9H), 10.84
(s, 0.1H), 7.76 (d, J=2.1 Hz, 1H), 7.57 (dd, J=2.2 Hz, 8.4 Hz, 1H),
7.23 (d, J=8.6 Hz, 1H), 7.12 (d, J=8.4 Hz, 2H), 6.61 (d, J=8.6 Hz,
1H), 5.51 (br s, 1H), 5.43 (s, 1H), 1.87 0.83(m, 13H), 3.23 (d,
J=5.1 Hz, 1H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.24H.sub.24N.sub.2O.sub.4ICl: 566.0; Found: 566.9(M+H).
Example 43
2-[7-Iodo-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro-benzo-
[e][1,4]diazepin-4-yl]-3-phenyl-propionic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.77 (s, 0.8H), 10.52
(s, 0.2H), 7.72 6.95 (m, 11H), 6.57 (d, J=8.6 Hz, 0.2H), 6.52 (d,
J=8.6 Hz, 0.8H), 5.58 (br s, 1.2H), 5.44 (s, 0.4H), 5.29 (s, 0.4H),
3.42 (d, J=5.5 Hz, 0.8H), 3.39 (d, J=5.5 Hz, 1.2H). Mass spectrum
(LCMS, ESI pos) Calcd. for C.sub.25H.sub.18N.sub.2O.sub.5IF.sub.3:
610.0; Found: 610.9(M+H).
Example 44
3-(4-Chloro-phenyl)-2-[7-iodo-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,-
3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-propionic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.76 (s, 0.8H), 10.54
(s, 0.2H), 7.72 6.95 (m, 10H), 6.57(d, J=8.6 Hz, 0.2H), 6.52 (d,
J=8.6 Hz, 0.8H), 5.59 (br s, 1.4H), 5.54 (s, 0.2H), 5.40 (s, 0.2H),
5.16 (s, 0.2H), 3.42 (d, J=5.2 Hz, 0.8H), 3.39 (d, J=5.2 Hz, 1.2H).
Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.25H.sub.17N.sub.2O.sub.5IF.sub.3: 644.0; Found:
644.8(M+H).
Example 45
3-(4-Hydroxy-phenyl)-2-[7-iodo-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2-
,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-propionic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.76 (s, 1H), 9.15
(s, 1H), 7.60 (d, J=1.6 Hz, 4H), 7.48 (dd, J=1.9 Hz, 8.4 Hz, 3H),
7.05 (m, 3H), 6.59 (d, J=8.5 Hz, 0.6H), 6.54 (d, J=8.5 Hz, 0.4H),
5.53 (br, s, 2H), 3.28 (m, 2H). Mass spectrum (LCMS, ESI pos)
Calcd. for C.sub.25H.sub.18N.sub.2O.sub.6IF.sub.3: 626.0; Found:
626.9(M+H).
Example 46
3-Cyclohexyl-2-[7-iodo-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tet-
rahydro-benzo[e][1,4]diazepin-4-yl]-propionic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.94 (s, 0.9H), 10.84
(s, 0.1H), 7.71 (d, J=1.9 Hz, 1H), 7.54 (dd, J=2.1 Hz, 8.4 Hz, 1H),
7.24 (d, J=8.4 Hz, 2H), 7.14 (d, J=8.4 Hz, 2H), 6.59 (d, J=8.6 Hz,
1H), 5.51 (br s, 2H), 1.87 0.83 (m, 13H). Mass spectrum (LCMS, ESI
pos) Calcd. for C.sub.25H.sub.24N.sub.2O.sub.5IF.sub.3: 616.1;
Found: 616.9(M+H).
Example 47
[1-Benzyl-3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e]-
[1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.62 6.97 (m, 17H),
6.22 (s, 0.6H), 6.19 (s, 0.4H), 5.65 (br s, 1H), 5.40 (m, 1H), 4.80
(m, 1H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.30H.sub.22N.sub.2O.sub.4ICl: 636.0; Found: 636.9(M+H).
Example 48
[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1-phenethyl-1,2,3,5-tetrahydro-benzo-
[e][1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.71 (s, 1H), 7.56 (m,
2H), 7.31 (m, 8H), 7.05 (m, 5H), 6.89 (s, 1H), 6.20 (s, 1H), 5.85
(s, 0.4H), 5.31 (s, 0.6H), 4.23 (m, 1H), 3.85 (m, 1H), 2.85 (m,
0.5H), 2.62 (m, 1.5H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.31H.sub.24N.sub.2O.sub.4ICl: 650.0; Found: 650.9(M+H).
Example 49
[3-(4-Chloro-phenyl)-7-iodo-1-isobutyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[-
e][1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.68 (m, 1H), 7.59 (m,
1H), 7.51 (d, J=6.5 Hz, 1H), 7.39 (m, 5H), 7.12 (m, 1H), 6.95 (m,
3H), 6.26 (s, 0.6H), 6.13 (s, 0.4H), 5.57 (s, 0.6H), 5.34 (s,
0.4H), 4.10 (m, 2H), 1.60 (m, 1H), 0.65 (m, 6H). Mass spectrum
(LCMS, ESI pos) Calcd. for C.sub.27H.sub.24N.sub.2O.sub.4ICl:
602.0; Found: 602.9(M+H).
Example 50
[3-(4-Chloro-phenyl)-7-iodo-1-(3-methyl-butyl)-2,5-dioxo-1,2,3,5-tetrahydr-
o-benzo[e][1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.68 (m, 1H), 7.53 (m,
2H), 7.30 (m, 4H), 7.06 (m, 3H), 6.87 (m, 1H), 6.26 (s, 1H), 6.04
(m, 1.6H), 5.35 (s, 0.4H) 4.07 (m, 1H), 3.44 (m, 1H), 1.40 (m, 1H),
1.24 (m, 1H), 1.13 (m, 1H), 0.75 (m, 6H). Mass spectrum (LCMS, ESI
pos) Calcd. for C.sub.28H.sub.26N.sub.2O.sub.4ICl: 616.1; Found:
616.9(M+H).
Example 51
[3-(4-Chloro-phenyl)-1-cyclobutylmethyl-7-iodo-2,5-dioxo-1,2,3,5-tetrahydr-
o-benzo[e][1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.65 (m, 1H), 7.58 (m,
1H), 7.49 (m, 2H), 7.40 (m, 4H), 7.11 (m, 2H), 6.95 (m, 2H), 6.23
(s, 0.7H), 6.10 (s, 0.7H), 5.56 (s, 0.3H), 5.33 (s, 0.3H), 4.18 (m,
1H), 3.52 (m, 1H), 2.19 (m, 1H), 1.68 (m, 4H), 1.40 (m, 2H). Mass
spectrum (LCMS, ESI pos) Calcd. for
C.sub.28H.sub.24N.sub.2O.sub.4ICl: 614.0; Found: 614.9(M+H).
Example 52
[3-(4-Chloro-phenyl)-1-cyclopentylmethyl-7-iodo-2,5-dioxo-1,2,3,5-tetrahyd-
ro-benzo[e][1,4]diazepin4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.66 (m, 1H), 7.53 (m,
3H), 7.38 (s, 1H), 7.25 (s, 4H), 7.02 (m, 3H), 6.85 (m, 1H), 6.34
(s, 0.7H), 6.10 (br s, 1H), 5.44 (s, 0.3H), 4.02 (m, 1.3H), 3.48
(m, 0.7H), 1.34 (m, 6H), 0.77 (m, 2H). Mass spectrum (LCMS, ESI
pos) Calcd. for C.sub.29H.sub.26N.sub.2O.sub.4ICl: 628.1; Found:
628.9(M+H).
Example 53
[3-(4-Chloro-phenyl)-1-cyclohexylmethyl-7-iodo-2,5-dioxo-1,2,3,5-tetrahydr-
o-benzo[e][1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.64 (m, 1H), 7.53 (m,
3H), 7.35 (s, 1H), 7.27 (s, 4H), 7.05 (m, 2H), 6.85 (m, 1H), 6.34
(s, 0.7H), 6.06 (br s, 1H), 5.47 (s, 0.3H), 4.98 (m, 0.7H), 3.23
(m, 1.3H), 1.53 0.6 (m, 11H). Mass spectrum (LCMS, ESI pos) Calcd.
for C.sub.30H.sub.28N.sub.2O.sub.4ICl: 642.9; Found: 643.0(M).
Example 54
[3-(4-Chloro-phenyl)-7-iodo-1-(2-methyl-benzyl)-2,5-dioxo-1,2,3,5-tetrahyd-
ro-benzo[e][1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.68 (s, 0.4H), 7.60
(s, 0.6H), 7.51 (d, J=7.4 Hz, 1H), 7.44 (m, 1H), 7.38 (s, 1H), 7.26
(m, 4H), 7.05 (m, 6H), 6.87 (m, 2H), 6.29 (s, 0.7H), 6.17 (s, 1H),
5.55 (s, 0.3H), 5.34 (d, J=15.8 Hz, 0.3H), 5.27 (d, J=15.8 Hz,
0.7H), 4.93 (d, J=15.8 Hz, 0.3H), 4.68 (d, J=15.8 Hz, 0.7H), 2.20
(s, 1H), 1.98 (s, 2H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.31H.sub.24N.sub.2O.sub.4ICl: 650.0; Found: 650.9(M+H).
Example 55
[3-(4-Chloro-phenyl)-7-iodo-1-(3-methyl-benzyl)-2,5-dioxo-1,2,3,5-tetrahyd-
ro-benzo[e][1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.62 (s, 0.4H), 7.59
(s, 0.6H), 7.52 (d, J=7.0 Hz, 1H), 7.45 (m, 3H), 7.26 (m, 3H), 7.09
(m, 5H), 6.90 (m, 3H), 6.74 (s, 0.6H), 6.34 (s, 0.4H), 6.17 (m,
1H), 5.53 (d, J=15.6 Hz, 0.4H), 5.27 (d, J=15.6 Hz, 0.6H), 4.83 (d,
J=15.6 Hz, 0.4H), 4.64 (d, J=15.6 Hz, 0.6H), 2.18 (s, 3H). Mass
spectrum (LCMS, ESI pos) Calcd. for
C.sub.31H.sub.24N.sub.2O.sub.4ICl: 650.0; Found: 650.9(M+H).
Example 56
[3-(4-Chloro-phenyl)-7-iodo-1-(4-methyl-benzyl)-2,5-dioxo-1,2,3,5-tetrahyd-
ro-benzo[e][1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.57 (m, 1H), 7.43 (m,
3H), 7.31 (m, 4H), 7.10 (m, 3H), 6.99 (m, 3H), 6.84 (m, 2H), 6.35
(s, 0.4H), 6.19 (s, 1H), 5.55 (d, J=15.1 Hz, 0.4H), 5.42 (s, 0.6H),
5.27 (d, J=15.1 Hz, 0.6H), 4.77 (d, J=15.1 Hz, 0.4H), 4.59 (d,
J=15.1 Hz, 0.6H), 2.20 (s, 3H). Mass spectrum (LCMS, ESI pos)
Calcd. for C.sub.31H.sub.24N.sub.2O.sub.4ICl: 650.0; Found:
650.9(M+H).
Example 57
[3-(4-Chloro-phenyl)-7-iodo-1-naphthalen-2-ylmethyl-2,5-dioxo-1,2,3,5-tetr-
ahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.79 (m, 4H), 7.58 (m,
2H), 7.46 (m, 4H), 7.31 (m, 2H), 7.15 (s, 2H), 7.05 (m, 1H), 6.90
(m, 1H), 6.36 (m, 0.6H), 6.23 (s, 1H), 5.76 (d, J=15.8 Hz, 0.4H),
5.47 (d, J=15.8 Hz, 0.6H), 5.44 (s, 0.4H), 5.00 (d, J=15.8 Hz,
0.4H), 4.84 (d, J=15.8 Hz, 0.6H), 2.20 (s, 3H). Mass spectrum
(LCMS, ESI pos) Calcd. for C.sub.34H.sub.24N.sub.2O.sub.4ICl:
686.0; Found: 686.9(M+H).
Example 58
[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1-pyridin-2-ylmethyl-1,2,3,5-tetrahy-
dro-benzo[e][1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.48 (m, 1H), 7.73 (m,
2H), 7.65 (m, 2H), 7.53 (m, 4H), 7.34 (m, 4H), 7.09 (m, 2H), 6.90
(m, 1H), 6.32 (s, 0.6H), 6.20 (s, 1H), 5.89 (br s, 0.4H), 5.36 4.89
(m, 2H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.29H.sub.21N.sub.3O.sub.4ICl: 637.0; Found: 638.0(M+H).
Example 59
[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1-pyridin-3-ylmethyl-1,2,3,5-tetrahy-
dro-benzo[e][1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.40 (m, 1H), 7.52 (m,
3H), 7.27 (m, 4H), 7.11 (m, 4H), 6.96 (m, 2H), 6.82 (m, 2H), 6.33
(s, 0.6H), 6.24 (s, 0.4H), 6.15 (s, 0.6H), 5.69 (m, 0.4H), 5.35 (s,
0.6H), 5.31 (m, 0.4H), 4.85 (m, 1H). Mass spectrum (LCMS, ESI pos)
Calcd. for C.sub.29H.sub.21N.sub.3O.sub.4ICl: 637.0; Found:
638.1(M+H).
Example 60
[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1-pyridin-4-ylmethyl-1,2,3,5-tetrahy-
dro-benzo[e][1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.41 (br s, 1H), 7.64
(m, 1H), 7.48 (m, 4H), 7.32 (m, 4H), 7.11 (m, 3H), 6.91 (m, 3H),
6.34 (s, 0.6H), 6.23 (s, 0.4H), 6.16 (s, 0.4H), 5.60 (d, J=15.5 Hz,
0.4H), 5.38 (s, 0.6H), 5.26 (d, J=15.5 Hz, 0.6H), 4.90 (d, J=15.5
Hz, 0.4H), 4.77 (d, J=15.5 Hz, 0.6H). Mass spectrum (LCMS, ESI pos)
Calcd. for C.sub.29H.sub.21N.sub.3O.sub.4ICl: 637.0; Found: 638.
1(M+H).
Example 61
(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-
-benzo[e][1,4]diazepin-4-yl]-acetic acid methyl ester
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.04 (m, 1.7H), 7.87 (m,
0.3H), 7.50 (s, 1H), 7.42 7.10 (m, 6H), 7.00 (m, 1H), 6.83 (s,
0.8H), 6.73 (d, J=8.4 Hz, 1.2H), 6.44 (d, J=8.4 Hz, 0.8H), 6.37 (d,
J=8.4 Hz, 0.2H), 5.34 (m, 0.2H), 5.28 (s, 0.8H), 3.84 (s, 0.6H),
3.83 (s, 2.4H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.24H.sub.17N.sub.2O.sub.4ICl.sub.2: 594.0; Found:
594.8(M+H).
Example 62
(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-
-benzo[e][1,4]diazepin-4-yl]-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.64 (s, 0.6H), 10.53
(s, 0.4H), 7.81 (s, 0.6H) 7.73 (s, 0.4H), 7.52 7.15 (m, 4H), 7.07
(d, J=7.9 Hz, 3H), 6.81 (m, 2H), 6.63 (d, J=8.6 Hz, 0.6H), 6.54 (d,
J=8.6 Hz, 0.4H), 6.25 (m, 1H), 5.81 (br s, 0.4H), 5.22 (s, 0.6H).
Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.23H.sub.15N.sub.2O.sub.4ICl.sub.2: 579.9; Found:
580.8(M+H).
Example 63
[3-(4-Chloro-phenyl)-7-iodo-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e]-
[1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.63 (m, 2H), 7.49 (m,
1H), 7.29 (m, 4H), 7.09 (s, 2H), 7.00 (d, J=7.7 Hz, 1H), 6.82 (m,
1H), 6.72 (m, 1H), 6.28 (m, 1H), 5.92 (s, 0.5H) 5.31 (s, 0.5H),
3.12 (s, 3H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.24H.sub.18N.sub.2O.sub.4ICl: 560.0; Found: 560.9(M+H).
Example 64
[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1-(3-phenyl-propyl)-1,2,3,5-tetrahyd-
ro-benzo[e][1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.70 (m, 1H), 7.49 (m,
3H), 7.17 (m, 11H), 6.80 (s, 2H), 6.36 (m, 0.6H), 6.15 (s, 0.4H),
6.01 (s, 0.6H), 5.31 (s, 0.4H), 4.50 (m, 1H), 4.34 (m, 1H), 2.31
(m, 1H), 2.24 (m, 1H), 1.58, (m, 1H), 1.45 (m, 1H). Mass spectrum
(LCMS, ESI pos) Calcd. for C.sub.32H.sub.26N.sub.2O.sub.4ICl:
664.1; Found: 665.2(M+H).
Example 65
2-{2-(4-Chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tet-
rahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-3-methyl-butyric
acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.80 7.75 (m, 1H),
7.58 7.40 (m, 5H), 7.17 7.11 (m, 2H), 6.97 (d, J=8.0 Hz, 1H), 6.92
(d, J=8.0 Hz, 1H), 6.67 6.52 (m, 2H), 5.15 (s, 0.5H) 4.94 (s,
0.5H), 4.07 3.95 (m, 1H), 2.05 (s 1H), 0.84 (d, J=6 Hz, 3H), 0.79
0.71 (m, 3H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.28H.sub.24Cl.sub.2IN.sub.3O.sub.5: 679.01; Found: 679.69
(M+H).
Example 66
3-[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]di-
azepin-4-yl]-3-phenyl-propionic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.90 (s, 0.8H), 10.71
(s, 0.2H), 7.81 (s, 1H) 7.66 (m, 1H), 7.61 7.53 (m, 3H), 7.42 7.27
(m, 4H), 6.99 (d, J=8.8 Hz, 1.6H), 6.61 (d, J=8.7 Hz, 0.4H), 6.50
(m, 2H), 5.24 (s, 1H), 3.18 (m 2H). Mass spectrum (LCMS, ESI pos)
Calcd. for C.sub.24H.sub.18N.sub.2O.sub.4ICl: 560.0; Found:
560.9(M+H).
Example 67
2-[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]di-
azepin-4-yl]-N-methyl-2-phenyl-acetamide
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.06 (d, J=2.1 Hz,
0.8H), 8.02 (m, 0.6H), 7.98 (s, 0.6H), 7.50 7.30 (m, 6H), 716 7.07
(m, 4H), 6.50 (m, 1H), 6.34 (d, J=8.4 Hz, 1H), 5.96 (m, 0.5H), 5.61
(s, 0.5H), 2.91 (s, 1.5H), 2.90 (s, 1.5H). Mass spectrum (LCMS, ESI
pos) Calcd. for C.sub.24H.sub.19N.sub.3O.sub.3ICl: 559.0; Found:
559.9(M+H).
Example 68
(7-Iodo-2,5-dioxo-3-pyridin-2-yl-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin--
4-yl)-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.60 (s, 0.6H), 10.52
(s, 0.4H), 8.56 (m, 0.4H), 8.46 (m, 0.6H), 8.06 (s, 0.4H), 7.85 (m,
1H), 7.76 (dd, J=2.2 Hz, 8.2 Hz, 1H), 7.61 (m, 0.6H), 7.51 (m, 1H),
7.40 (m, 2H), 7.30 (m, 1H), 7.10 (m, 2H), 6.70 (m, 2H), 6.63 (d,
J=8.6 Hz, 0.6H), 6.56 (d, J=8.6 Hz, 0.4H), 5.67 (s, 0.4H), 5.58 (s,
0.6H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.22H.sub.16N.sub.3O.sub.4I: 513.0; Found: 514.0(M+H).
Example 69
(7-Iodo-2,5-dioxo-3-pyridin-3-yl-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin--
4-yl)-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.72 (s, 0.5H), 10.56
(s, 0.5H), 8.33 (m, 1H), 8.35 7.00 (m, 10H), 6.63 (d, J=8.6 Hz,
0.6H), 6.56 (d, J=8.6 Hz, 0.4H), 6.35 (s, 1H), 5.82 (s, 0.4H),
5.30(s, 0.6H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.22H.sub.16N.sub.3O.sub.4I: 513.0; Found: 514.1(M+H).
Example 70
(7-Iodo-2,5-dioxo-3-thiophen-3-yl-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-
-4-yl)-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.59 (s, 0.9H), 10.43
(s, 0.1H), 7.78 (s, 1H), 7.54 (m, 3H), 7.35 (m, 4H), 715 (m, 1H),
6.72 (m, 1H), 6.38 (s, 1H), 6.30 (s, 1H), 5.15 (s, 0.1H), 5.12 (s,
0.9H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.21H.sub.15N.sub.2O.sub.4IS: 518.0; Found: 518.9(M+H).
Example 71
[7-Iodo-3-(5-methyl-thiophen-2-yl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1-
,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.56 (s, 1H), 7.83
(s, 1H), 7.61 (m, 1H), 7.45 (m, 2H), 7.33 (m, 3H), 6.76 (d, J=8.6
Hz, 1H), 6.33 (s, 1H), 6.23 (m, 1H), 6.02 (s, 1H), 5.24 (s, 1H),
2.11 (s, 3H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.22H.sub.17N.sub.2O.sub.4IS: 532.0; Found: 532.9(M+H).
Example 72
[7-Iodo-3-(3-methyl-thiophen-2-yl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1-
,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.54 (s, 1H), 7.99
(s, 1H), 7.68 (m, 1H), 7.34 (m, 4H), 7.00 (m, 1H), 6.77 (m, 1H),
6.39 (m, 1H), 6.27 (s, 1H), 6.02 (s, 1H), 5.36 (s, 1H), 1.69 (s,
3H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.22H.sub.17N.sub.2O.sub.4IS: 532.0; Found: 532.8(M+H).
Example 73
[3-(4-Bromo-thiophen-2-yl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,-
4]diazepin-4-yl ]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.71 (s, 0.7H), 10.57
(s, 0.3H), 7.83 (d, J=2.2 Hz, 0.7H), 7.77 (d, J=2.2 Hz, 0.3H), 7.65
(m, 1H), 7.47 (d, J=7.0 Hz, 2H), 7.33 (m, 4H), 7.00 (m, 1H), 6.78
(d, J=8.6 Hz, 0.7H), 6.68 (d, J=8.6 Hz, 0.3H), 6.36 (s, 0.7H), 6.24
(s, 0.3H), 5.87 (s, 0.3H), 5.32 (s, 0.7H). Mass spectrum (LCMS, ESI
pos) Calcd. for C.sub.21H.sub.14N.sub.2O.sub.4ISBr: 595.9; Found:
596.8(M+H).
Example 74
(3-[2,2']Bithiophenyl-5-yl-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,-
4]diazepin-4-yl)-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.73 (s, 0.8H), 10.57
(s, 0.2H), 7.86 (d, J=2.0 Hz, 0.8H), 7.79 (d, J=2.0 Hz, 0.2H), 7.63
(m, 1H), 7.52 (d, J=7.4 Hz, 2H), 7.39 (m, 5H), 7.01 (m, 1H), 6.79
(m, 2H), 6.40 (s, 1H), 6.27 (m, 1H), 5.88 (s, 0.2H), 5.30 (s,
0.8H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.25H.sub.17N.sub.2O.sub.4IS.sub.2: 600.0; Found:
601.9(M+H).
Example 75
[7-Iodo-3-(3-methyl-benzo[b]thiophen-2-yl)-2,5-dioxo-1,2,3,5-tetrahydro-be-
nzo[e][1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.74 (s, 0.5H), 10.56
(s, 0.5H), 8.00 (s, 1H), 7.69 (m, 2H), 7.46 (m, 2H), 7.26 (m, 4H),
6.94 (m, 1H), 6.77 (m, 1H), 6.70 (s, 0.5H), 6.63 (d, J=8.6 Hz, 1H),
6.28 (s, 0.5H), 5.60 (s, 0.5H), 5.48 (s, 0.5H), 1.90 (s, 3H). Mass
spectrum (LCMS, ESI pos) Calcd. for
C.sub.26H.sub.19N.sub.2O.sub.4IS: 582.0; Found: 583.9(M+H).
Example 76
{3-[5-(2-Chloro-phenyl)-furan-2-yl]-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-be-
nzo[e][1,4]diazepin-4-yl}-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.70 (s, 0.8H), 10.59
(s, 0.2H), 7.90 (d, J=2.1 Hz, 1H), 7.70 (dd, J=2.1 Hz, 8.3 Hz, 2H),
7.37 (m, 5H), 6.85 (m, 4H), 6.67 (d, J=3.5 Hz 1H), 6.41 (s, 1H),
5.62 (s, 1H), 5.32 (s, 1H.). Mass spectrum (LCMS, ESI pos) Calcd.
for C.sub.27H.sub.18N.sub.2O.sub.5ICl: 612.0; Found:
613.1(M+H).
Example 77
{3-[5-(3-Chloro-phenyl)-furan-2-yl]-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-be-
nzo[e][1,4]diazepin-4-yl}-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.70 (s, 1H), 7.91
(d, J=2.3 Hz, 2H), 7.68 (dd, J=2.1 Hz, 8.3 Hz, 2H), 7.49 (d, J=7.2
Hz, 2H), 7.30 (m, 5H), 6.89 (d, J=8.6 Hz, 1H), 6.63 (d, J=3.5 Hz,
1H), 6.44 (s, 1H), 5.49 (s, 1H), 5.35 (s, 1H.). Mass spectrum
(LCMS, ESI pos) Calcd. for C.sub.27H.sub.18N.sub.2O.sub.5ICl:
612.0; Found: 612.9(M+H).
Example 78
(7-Iodo-2,5-dioxo-3-quinolin-3-yl-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-
-4-yl)-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.72 (s, 0.8H), 10.61
(s, 0.2H), 9.02 (d, J=2.0 Hz, 1.5H), 8.82 (d, J=2.0 Hz, 0.5H), 8.45
(s, 1.5H), 8.36 (s, 0.5H), 8.05 (d, J=8.5 Hz, 1.5H), 7.98 (d, J=8.5
Hz, 0.5H), 7.84 6.84 (m, 7H), 6.72 (s, 0.8H), 6.62 (d, J=8.6 Hz,
0.8H), 6.56 (d, J=8.6 Hz, 0.2H), 6.45 (s, 0.2H), 5.68 (s, 0.2H),
5.10 (s, 0.8H.). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.26H.sub.18N.sub.3O.sub.4I: 563.0; Found: 564.1(M+H).
Example 79
[7-Bromo-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]dia-
zepin-4-yl]-(4-chloro-phenyl)-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.79 (s, 0.5H), 10.63
(s, 0.5H), 7.58 (m, 1H) 7.52 (d, J=8.6 Hz 1H), 7.41 (m, 4H), 7.17
(m, 3H), 6.98 (m, 1H), 6.79 (d, J=8.6 Hz, 0.5H), 6.72 (d, J=8.6 Hz,
0.5H), 6.29 (s, 0.5H), 6.24 (s, 0.5H), 5.68 (s, 0.5H), 5.23 (s,
0.5H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.23H.sub.15N.sub.2O.sub.4BrCl.sub.2: 534.0; Found:
534.9(M+H).
Example 80
2-[7-Bromo-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]d-
iazepin-4-yl]-3-(4-trifluoromethyl-phenyl)-propionic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.77 (s, 0.8H), 10.51
(s, 0.2H), 7.30 7.20 (m, 6H), 7.35 (m, 1H), 7.15 (m, 3H), 6.96 (m,
2H), 6.72 (m, 1H), 5.60 (br s, 2H). Mass spectrum (LCMS, ESI pos)
Calcd. for C.sub.25H.sub.17N.sub.2O.sub.4BrF.sub.3Cl: 580.0; Found:
581.0(M+H).
Example 81
2-[7-Bromo-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]d-
iazepin-4-yl]-3-phenyl-propionic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.81 (s, 0.8H), 10.56
(s, 0.2H), 7.48 (s, 1H) 7.42 7.30 (m, 4H), 7.22 (m, 3H), 7.13 (m,
2H), 6.95 (m, 1H), 6.69 (m, 1H), 5.54(m, 1.4H), 5.40 (s, 0.3H),
5.30 (br s, 0.3H), 3.40 (m, 1.5H), 3.20 (m, 0.5H). Mass spectrum
(LCMS, ESI pos) Calcd. for C.sub.24H.sub.18N.sub.2O.sub.4BrCl:
512.0; Found: 513.0(M+H).
Example 82
2-[7-Bromo-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]d-
iazepin-4-yl]-3-(4-chloro-phenyl)-propionic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.80 (s, 0.8H), 10.58
(s, 0.2H), 7.50 (s, 1H), 7.43 7.37 (m, 3H), 7.22 7.12 (m, 4H), 6.92
(m, 2H), 6.69 (m, 1H), 5.57(m, 0.8H), 5.53 (s, 0.8H), 5.37 (s,
0.2H), 5.16 (br s, 0.2H), 3.40 (m, 1.5H), 3.20 (m, 0.5H). Mass
spectrum (LCMS, ESI pos) Calcd. for
C.sub.24H.sub.17N.sub.2O.sub.4BrCl.sub.2: 546.0; Found: 547.0
(M+H).
Example 83
2-(4-Chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrah-
ydro-benzo[e][1,4]diazepin-4-yl]-acetamide
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.75 (s, 0.6H), 10.65
(s, 0.4H), 7.77 (m, 1H), 7.71 (m, 1H), 7.56 (m, 1H), 7.52 7.45 (m,
3H), 7.38 7.07 (m, 4H), 6.91 (d, J=8.4 Hz, 1H), 6.64 6.55 (m, 1H),
6.41 (s, 0.6H), 5.51 (s, 0.4H), 4.96 (s, 0.6H), 4.70 (s, 0.4H).
Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.23H.sub.16N.sub.3O.sub.3ICl.sub.2: 579.0; Found:
580.1(M+H).
Example 84
[7-Chloro-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]di-
azepin-4-yl]-(4-chloro-phenyl)-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.77 (s, 0.8H), 10.61
(s, 0.2H), 7.52 (m, 1H) 7.46 7.39 (m, 4H), 7.32 (m, 2H), 7.15 (d,
J=9.0 Hz, 2H), 6.97 (m, 1H), 6.86 (d, J=8.4 Hz, 0.6H), 6.78 (d,
J=8.4 Hz, 0.4H), 6.28 (s, 0.4H), 6.23 (s, 0.6H), 5.72 (br s, 0.4H),
5.23 (s, 0.6H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.23H.sub.15N.sub.2O.sub.4Cl.sub.3: 488.0; Found:
489.0(M+H).
Example 85
(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-methyl-2,5-dioxo-1,2,3,5-tetrahyd-
ro-benzo[e][1,4]diazepin-4-yl]-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.53 (s, 0.6H), 10.37
(s, 0.4H), 7.50 (d, J=8.4 Hz, 1H), 7.41 7.29 (m, 4H), 7.17 7.00 (m,
4H), 6.91 (m, 1H), 6.72 (d, J=8.4 Hz, 0.6H), 6.64 (d, J=8.4 Hz,
0.4H), 6.34 (s, 0.4H), 6.25 (s, 0.6H), 5.71 (s, 0.4H), 5.25 (s,
0.6H), 2.14 (s, 2H), 2.12 (s, 1H). Mass spectrum (LCMS, ESI pos)
Calcd. for C.sub.24H.sub.18N.sub.2O.sub.4Cl.sub.2: 468. 1; Found:
469.0(M+H).
Example 86
(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-naphth-
o[2,3-e][1,4]diazepin-4-yl]-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.79 (s, 0.6H), 10.64
(s, 0.4H), 8.21 (s, 0.6H), 8.17 (s, 0.4H), 7.88 (m, 3H), 7.69 (m,
1H), 7.55 (d, J=8.4 Hz, 1H), 7.49 7.39 (m, 4H), 7.29 (s, 1H), 7.21
(m, 1H), 7.01 (m, 2H), 6.41 (s, 0.4H), 632 (s, 0.6H), 5.81 (s,
0.4H), 5.32 (s, 0.6H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.27H.sub.18N.sub.2O.sub.4Cl.sub.2: 504.1; Found:
505.0(M+H).
Example 87
[8-Chloro-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]di-
azepin-4-yl]-(4-chloro-phenyl)-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.73 (s, 0.8H), 10.58
(s, 0.2H), 7.52 (m, 2H), 7.40 (m, 1H), 7.14 (m, 4H), 7.00 (m, 1H),
6.91 (m, 3H), 6.30 (s 0.2H), 6.25 (s, 0.8H) 5.76 (s, 0.2H), 5.22
(s, 0.8H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.23H.sub.15N.sub.2O.sub.4Cl.sub.3: 488.0; Found:
489.0(M+H).
Example 88
(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-ethynyl-2,5-dioxo-1,2,3,5-tetrahy-
dro-benzo[e][1,4]diazepin-4-yl]-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.83 (s, 0.5H), 10.66
(s, 0.5H), 7.52 (m, 2H) 7.43 7.29 (m, 4H), 7.15 (m, 3H), 6.96 (m,
1H), 6.83 (d, J=8.4 Hz, 0.6H), 6.75 (d, J=8.4 Hz, 0.4H), 6.29 (s,
0.4H), 6.23 (s, 0.6H), 5.74 (br s, 0.4H), 5.21 (s, 0.6H), 4.16 (s,
0.6H), 4.14 (s, 0.4H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.23H.sub.16N.sub.2O.sub.4ICl.sub.2: 478.0; Found:
479.0(M+H).
Example 89
[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diaz-
epin-4-yl]-p-tolyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.64 (s, 0.8H), 10.46
(s, 0.2H), 7.81 (s, 1H), 7.50 (m, 2H), 7.36 (d, J=7.9 Hz, 2H), 7.20
(m, 1H), 7.08 (m, 3H), 6.81 (d, J=8.4 Hz, 1H), 6.63 (d, J=8.6 Hz,
1H), 6.27 (s, 1H), 5.83 (br s, 0.2H), 5.16 (s, 0.8H), 2.22 (s, 3H).
Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.24H.sub.18N.sub.2O.sub.4ICl: 560.0; Found: 561.0(M+H).
Example 90
(4-Chloro-3-fluoro-phenyl)-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-t-
etrahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.65 (s, 0.9H), 10.60
(s, 0.1H), 7.79 (s, 1H), 7.52 (m, 3H), 7.35 (m, 2H), 7.13 (m, 2H),
6.95 (d, J=8.0 Hz, 1H), 6.63 (d, J=8.6 Hz, 1H), 6.29 (s, 0.1H),
6.14 (s, 0.9H), 5.80 (s, 0.1H), 5.29 (s, 0.9H). Mass spectrum
(LCMS, ESI pos) Calcd. for
C.sub.23H.sub.14N.sub.2O.sub.4ICl.sub.2F: 597.9; Found:
598.9(M+H).
Example 91
[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diaz-
epin-4-yl]-(2-fluoro-4-trifluoromethyl-phenyl)-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.65 (br s, 1H), 7.80
(s, 1H), 7.74 7.53 (m, 5H), 7.12 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.1
Hz, 1H), 6.63 (d, J=8.6 Hz, 1H), 6.45 (s, 1H), 5.60 (s, 0.1H), 5.24
(s, 0.9H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.24H.sub.14N.sub.2O.sub.4IClF.sub.4: 632.0; Found:
633.0(M+H).
Example 92
(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-ethyl-2,5-dioxo-1,2,3,5-tetrahydr-
o-benzo[e][1,4]diazepin-4-yl]-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.50 (s, 0.8H), 10.32
(s, 0.2H), 7.52 (d, J=8.4 Hz, 1H), 7.36 (m, 3H), 7.17 7.03 (m, 4H),
6.83 (d, J=8.0 Hz, 1H), 6.63 (d, J=8.6 Hz, 1H), 6.72 (d, J=8.4 Hz,
1H), 6.37 (s, 0.2H), 6.29 (m, 0.8H), 5.74 (s, 0.2H), 5.26 (s,
0.8H), 2.42 (m, 2H), 1.00 (m, 3H). Mass spectrum (LCMS, ESI pos)
Calcd. for C.sub.25H.sub.20N.sub.2O.sub.4Cl.sub.2: 482.1; Found:
483.1(M+H).
Example 93
(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-isopropyl-2,5-dioxo-1,2,3,5-tetra-
hydro-benzo[e][1,4]diazepin-4-yl]-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.49 (s, 0.8H), 10.27
(s, 0.2H), 7.53 (d, J=8.4 Hz, 1H) 7.36 (m, 2H), 7.17 7.03 (m, 3H),
6.98 (d, J=8.4 Hz, 1H), 6.78 (d, J=8.1 Hz, 1H), 6.72 (d, J=8.4 Hz,
1H), 6.38 (s, 0.2H), 6.31 (m, 0.8H), 5.76 (s, 0.2H), 5.29 (s,
0.8H), 2.72 (m, 1H), 1.02 (m, 6H). Mass spectrum (LCMS, ESI pos)
Calcd. for C.sub.25H.sub.2O.sub.4N.sub.2O.sub.4Cl.sub.2: 496.1;
Found: 497.1(M+H).
Example 94
[7-tert-Butyl-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,-
4]diazepin-4-yl]-(4-chloro-phenyl)-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.45 (s, 0.8H), 10.25
(s, 0.2H), 7.52 (d, J=8.4 Hz, 1H), 7.44 (m, 1H), 7.40 7.31 (m, 3H),
7.22 7.03 (m, 3H), 6.98 (d, J=8.6 Hz, 1H), 6.78 (d, J=8.4 Hz, 1H),
6.72 (d, J=8.6 Hz, 1H), 6.37 (s, 0.2H), 6.29 (m, 0.8H), 5.75 (s,
0.2H), 5.27 (s, 0.8H), 1.13 (s, 8H), 1.11 (s, 1H). Mass spectrum
(LCMS, ESI pos) Calcd. for C.sub.27H.sub.24N.sub.2O.sub.4Cl.sub.2:
510.1; Found: 511.1(M+H).
Example 95
[3-(4-Chloro-phenyl)-7-ethyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]dia-
zepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.58 (s, 1H), 7.48
(d, J=7.0 Hz, 1H), 7.35 (m, 6H), 7.09 (d, J=8.6 Hz, 2H), 6.92 (d,
J=8.1 Hz, 2H), 6.74 (d, J=8.1 Hz, 1H), 6.32 (s, 1H), 5.12 (s, 1H),
2.43 (q, J=7.7 Hz, 2H), 1.00 (t, J=7.5 Hz, 3H). Mass spectrum
(LCMS, ESI pos) Calcd. for C.sub.25H.sub.21N.sub.2O.sub.4Cl.sub.2:
448.1; Found: 449.1(M+H).
Example 96
[3-(4-Chloro-phenyl)-7-isopropyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4-
]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.55 (s, 1H), 7.48
(d, J=7.0 Hz, 2H), 7.35(m, 3H), 7.07 (m, 3H), 6.91 (d, J=8.4 Hz,
2H), 6.73 (d, J=8.4 Hz, 2H), 6.31 (s, 1H), 5.11 (s, 1H), 2.74 (m,
1H), 1.03 (d, J=7.0 Hz, 6H). Mass spectrum (LCMS, ESI pos) Calcd.
for C.sub.26H.sub.23N.sub.2O.sub.4Cl: 462.1; Found: 463.1(M+H).
Example 97
[7-tert-Butyl-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,-
4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.54 (s, 1H), 7.50
(d, J=7.0 Hz, 2H), 7.37 (m, 3H), 7.24 (dd, J=2.4, 8.6 Hz, 2H), 7.06
(d, J=8.6 Hz, 2H), 6.90 (d, J=7.9 Hz, 2H), 6.72 (d, J=8.6 Hz, 1H),
6.32 (s, 1H), 5.10 (m, 1H), 1.13 (s, 9H). Mass spectrum (LCMS, ESI
pos) Calcd. for C.sub.27H.sub.25N.sub.2O.sub.4Cl.sub.2: 476.2;
Found: 477.1(M+H).
Example 98
[7-sec-Butyl-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4-
]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.51 (s, 1H), 7.49
(d, J=7.0 Hz, 2H), 7.36 (m, 4H), 7.20 (m, 1H), 7.03 (m, 3H), 6.86
(m, 1H), 6.73 (m, 1H), 6.31 (s, 1H), 5.11 (s, 1H), 2.45 (m, 1H),
1.44 (m, 1H), 1.28 (m, 1H), 1.06 (m, 3H), 0.45 (m, 3H). Mass
spectrum (LCMS, ESI pos) Calcd. for
C.sub.27H.sub.25N.sub.2O.sub.4Cl: 476.2; Found: 477.1(M+H).
Example 99
[7-sec-Butyl-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4-
]diazepin-4-yl]-(4-chloro-phenyl)-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.54 (s, 1H), 7.53
(d, J=8.6 Hz, 2H), 7.44 (m, 3H), 7.21 6.99 (m, 5H), 6.71 (m, 1H),
6.19 (s, 1H), 5.23 (s, 1H), 2.44 (m, 1H), 1.45 (m, 1H), 1.29 (m,
1H), 1.05 (m, 3H), 0.45 (m, 3H). Mass spectrum (LCMS, ESI pos)
Calcd. for C.sub.27H.sub.24N.sub.2O.sub.4Cl.sub.2: 510.1; Found:
511.1(M+H).
Example 100
(4-Bromo-phenyl)-[3-(4-chloro-phenyl)-7-isopropyl-2,5-dioxo-1,2,3,5-tetrah-
ydro-benzo[e][1,4]diazepin-4-yl]-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.53 (s, 0.7H), 10.34
(s, 0.3H), 7.54 (m, 2H), 7.46 (d, J=8.6 Hz, 2H), 7.36 7.24(m, 2H),
7.09 (m, 3H), 6.96 (m, 1H), 6.72 (d, J=8.4 Hz, 0.7H), 6.64 (d,
J=8.4 Hz, 0.3H), 6.30 (s, 0.3H), 6.17 (s, 0.7H), 5.65 (s, 0.3H),
5.24 (s, 0.7H), 2.72 (m, 1H), 1.03 (m, 6H). Mass spectrum (LCMS,
ESI pos) Calcd. for C.sub.26H.sub.22N.sub.2O.sub.4ClBr: 540.0;
Found: 541.0(M+H).
Example 101
[3-(4-Bromo-phenyl)-7-isopropyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]-
diazepin-4-yl]-(4-chloro-phenyl)-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.52 (s, 0.7H), 10.34
(s, 0.3H), 7.52 (d, J=8.4 Hz, 1H), 7.41 (m, 3H), 7.28 7.21(m, 3H),
7.12 7.03 (m, 2H), 6.91 (m, 1H), 6.72 (d, J=8.6 Hz, 0.7H), 6.64 (d,
J=8.6 Hz, 0.3H), 6.30 (s, 0.3H), 6.17 (s, 0.7H), 5.65 (s, 0.3H),
5.24 (s, 0.7H), 2.73 (m, 1H), 1.03 (m, 6H). Mass spectrum (LCMS,
ESI pos) Calcd. for C.sub.26H.sub.22N.sub.2O.sub.4ClBr: 540.0;
Found: 541.0(M+H).
Example 102
(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-cyclopropyl-2,5-dioxo-1,2,3,5-tet-
rahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.53 (s, 0.7H), 10.35
(s, 0.3H), 7.50 (d, J=8.4 Hz, 1H), 7.39 (m, 2H), 7.21 7.09 (m, 4H),
6.92 (m, 3H), 6.70 (d, J=8.4 Hz, 0.7H), 6.61 (d, J=8.4 Hz, 0.3H),
6.31 (s, 0.3H), 6.22 (s, 0.7H), 5.67 (s, 0.3H), 5.23 (s, 0.7H),
1.80 (m, 1H), 0.86 (m, 2H), 0.5 (m, 1H), 0.42 (m, 1H). Mass
spectrum (LCMS, ESI pos) Calcd. for
C.sub.26H.sub.20N.sub.2O.sub.4Cl.sub.2: 494.1; Found:
495.0(M+H).
Example 103
[3-(4-Chloro-phenyl)-7-cyclopropyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1-
,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.51 (s, 0.7H), 10.30
(s, 0.3H), 7.47 (d, J=7.0 Hz, 2H), 7.38 7.08 (m, 5H), 7.04 (d,
J=8.6 Hz, 2H), 6.88 (m, 2H), 6.70 (d, J=8.4 Hz, 0.7H), 6.61 (d,
J=8.4 Hz, 0.3H), 6.34 (br s, 1H), 5.71 (s, 0.3H), 5.16 (s, 0.7H),
1.79 (m, 1H), 0.85 (m, 2H), 0.53 (m, 1H), 0.44(m, 1H). Mass
spectrum (LCMS, ESI pos) Calcd. for
C.sub.26H.sub.21N.sub.2O.sub.4Cl: 460.1; Found: 461.1(M+H).
Example 104
[3-(4-Chloro-3-fluoro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e]-
[1,4]diazepin-4-yl]-(4-chloro-phenyl)-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.56 (s, 0.9H), 10.36
(s, 0.1H), 7.50 (m, 3H), 7.34 (m, 2H), 7.17 (m, 2H), 7.05 6.80 (m,
3H), 6.37 (s, 1H), 5.19 (s, 1H). Mass spectrum (LCMS, ESI pos)
Calcd. for C.sub.23H.sub.14N.sub.2O.sub.4Cl.sub.2F: 597.9; Found:
598.9(M+H).
Example 105
(2,5-Dioxo-3-phenyl-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-phenyl--
acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.79 (s, 0.9H), 10.61
(s, 0.1H), 7.77 (s, 1H), 7.53 (m, 4H), 7.38 (m, 4H), 7.03 (m, 2H),
6.81 (m, 2H), 6.67 (d, J=8.6 Hz, 0.9H), 6.58 (d, J=8.6 Hz, 0.1H),
6.27 (s, 0.1H), 6.16 (s, 0.9H), 5.64 (s, 0.1H), 5.30 (s, 0.9H).
Mass spectrum (LCMS, ESI pos) Calcd. for C.sub.23H.sub.18N.sub.2O:
386.1; Found: 387.1(M+H).
Example 106
[3-(4-Chlorophenyl)-7-phenyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]dia-
zepin-4-yl]-phenylacetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.60 (s, 0.8H), 10.50
(s, 0.2H), 7.82 (s, 1H), 7.52 (m, 4H), 7.41(m, 2H), 7.33 (m, 5H),
7.02 (d, J=8.2 Hz, 2H), 6.91 (d, J=8.3 Hz, 1H), 6.82 (m, 2H), 6.39
(bs, 1H), 5.25 (bs, 1H). Mass spectrum (LCMS, ESI pos.) Calcd. For
C.sub.29H.sub.21ClN.sub.2O.sub.4: 496.10. Found: 497.0 (M+H).
Example 107
[3-(4-Chlorophenyl)-7-(4-methylphenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[-
e][1,4]diazepin-4-yl]-phenylacetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.67 (bs, 1H), 7.77
(m, 1H), 7.49 (m, 3H), 7.41 (m, 4H), 7.25 (m, 4H), 7.06 (m, 2H),
6.90 (d, J=8.9 Hz, 2H), 6.39 (bs, 1H), 5.20 (bs 1H), 2.32 (s, 3H).
Mass spectrum (LCMS, ESI pos.) Calcd. For
C.sub.30H.sub.23ClN.sub.2O.sub.4: 510.10. Found: 511.0 (M+H).
Example 108
[3-(4-Chlorophenyl)-7-(3-methylphenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[-
e][1,4]diazepin-4-yl]-phenylacetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.60 (bs, 1H), 7.92
(m, 1H), 7.63 (m, 2H), 7.43 (m, 4H), 7.29 (m, 5H), 7.16 (m, 1H),
7.04 (m, 1H), 6.89 (m, 2H), 6.53 (bs, 1H), 5.40 (bs, 1H), 2.40 (s,
3H). Mass spectrum (LCMS, ESI pos.) Calcd. For
C.sub.30H.sub.23ClN.sub.2O.sub.4: 510.10. Found: 511.0 (M+H).
Example 109
[3-(4-Chlorophenyl)-7-(4-hydroxyphenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo-
[e][1,4]diazepin-4-yl]-phenylacetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.73 (bs, 0.85H),
10.56 (s, 0.15H), 9.62 (s, 1H), 7.68 (s, 1H), 7.52 (m, 3H), 7.36
(m, 4H), 7.17 (m, 1H), 7.10 (m, 2H), 6.97 (d, J=7.7 Hz, 2H), 6.87
(d, J=8.5 Hz, 2H), 6.81 (d, J=8.6 Hz, 2H), 6.37 (bs, 1H), 5.14 (bs,
1H), 2.40. Mass spectrum (LCMS, ESI pos.) Calcd. For
C.sub.29H.sub.21ClN.sub.2O.sub.5: 512.15. Found: 513.1 (M+H).
Example 110
[3-(4-Chlorophenyl)-7-(4-hydroxycarbonylphenyl)-2,5-dioxo-1,2,3,5-tetrahyd-
ro-benzo[e][1,4]diazepin-4-yl]-phenylacetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 13.1 (bs, 1H), 10.80
(bs, 0.4H), 10.59 (s, 0.6H), 7.98 (d, J=6.5 Hz, 2H), 7.85 (d, J=9.5
Hz, 1H), 7.65 (m, 3H), 7.50 (d, J=8.0 Hz, 1H), 7.34 (m, 4H), 7.24
(d, J=7.2 Hz, 1H), 7.14 (d, J=8.6 Hz, 1H), 7.07 (d, J=7.7 Hz, 1H),
6.94 (m, 1H), 6.37 (d, J=14.8 Hz, 1H), 5.76 (s, 1H). Mass spectrum
(LCMS, ESI pos.) Calcd. For C.sub.30H.sub.21ClN.sub.2O.sub.6:
540.16. Found: 541.0 (M+H).
Example 111
(4-Chlorophenyl)-[3-(4-chlorophenyl)-7-iodo-5-oxo-1,2,3,5-tetrahydro-benzo-
[e][1,4]diazepin-4-yl]acetic acid
.sup.1H NMR (400 MHz, d.sub.6-DMSO): Major (75%): .delta. 8.25 (d,
J=2.2 Hz, 1H), 7.22 (d, J=8.4 Hz, 2H), 7.19 (dd, J=8.8 Hz, J=2.2
Hz, 1H), 7.08 (d, J=8.3 Hz, 2H), 6.99 (d, J=8.4 Hz, 2H), 6.93 (br
m, 1H), 6.77 (d, J=7.9 Hz, 2H), 6.27 (d, J=8.7 Hz, 1H), 6.15 (br s,
1H), 5.02 (s, 1H), 3.89 (br m, 2H). Minor (25%): 7.97 (d, J=2.1 Hz,
1H), 7.43 (d, J=8.6 Hz, 2H), 7.36 (d, J=8.5 Hz, 1H), 7.14 (d, J=8.4
Hz, 2H), 7.11 (dd, J=8.8 Hz, J=2.2 Hz, 2H), 6.93 (br m, 1H), 6.19
(d, J=8.8 Hz, 1H), 6.15 (br s, 1H), 5.23 (s, 1H), 3.89 (br m, 2H).
Mass Spectrum (LCMS, ESI pos.): Calcd. For
C.sub.23H.sub.17Cl.sub.2IN.sub.2O.sub.3: 565.97; found: 566.94
(M+H).
Example 112
[3-(4-Chlorophenyl)-2,5-dioxo-8-phenyl-1,2,3,5-tetrahydro-benzo[e][1,4]dia-
zepin-4-yl]-phenylacetic acid
.sup.1H NMR (400 MHz, d.sub.6-DMSO): .delta. 10.41 (s, 1H), 7.73
7.61 (m, 1H), 7.57 7.32 (m, 8H), 7.28 7.02 (m, 5H), 6.98 (d, J=8.7
Hz, 1H), 6.72 (d, J=7.8 Hz, 1H), 6.32 (s, 1H), 5.29 (s, 1H). Mass
Spectrum (LCMS, ESI pos.): Calcd. for
C.sub.29H.sub.21ClN.sub.2O.sub.4: 496.12; found: 497.12 (M+H).
Example 113
[7-Benzo[1,3]dioxol-5-yl-2,5-dioxo-3-(4-trifluoromethyl-phenyl)-1,2,3,5-te-
trahydro-benzo[e][1,4]diazepin-4-yl]-phenylacetic acid
.sup.1H NMR (400 MHz, d.sub.6-DMSO): Major (67%): .delta. 10.84 (s,
1H), 7.65 (d, J=2.1 Hz, 1H), 7.56 7.34 (m, 9H), 7.23 (d, J=8.1 Hz,
1H), 7.05 (s, 1H), 6.99 6.93 (m, 2H), 6.86 (d, J=8.5 Hz, 1H), 6.37
(s, 1H), 5.20 (s, 1H). Minor (33%): 10.69 (s, 1H), 7.70 (d, J=2.1
Hz, 1H), 7.56 7.34 (m, 9H), 7.23 (d, J=8.1 Hz, 1H), 7.09 (s, 1H),
6.99 6.93 (m, 2H), 6.81 (d, J=8.3 Hz, 1H), 6.34 (s, 1H), 5.40 (s,
1H). Mass Spectrum (LCMS, ESI pos.): Calcd. for
C.sub.31H.sub.21F.sub.3N.sub.2O.sub.6: 574.14; found: 574.98
(M+H).
Example 114
3-(4-Chloro-phenyl)-3-[3-(4-chloro-phenyl)-7-iodo-5-oxo-1,2,3,5-tetrahydro-
-benzo[e][1,4]diazepin-4-yl]-propionic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.17 (d, J=2.0 Hz,
1H), 7.33 (d, J=8.8 Hz, 2H), 7.19 6.96 (m, 4H), 6.75 (d, J=8.8Hz,
1H), 6.39 6.29 (m, 1H), 6.21 (d, J=8.8 Hz, 1H), 4.92 (d, J=5.2 Hz,
1H), 4.08 3.96 (m, 1H), 3.46 3.36 (m, 2H), 2.93 2.75 (m, 2H).
Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.24H.sub.19Cl.sub.2IN.sub.2O.sub.3: 579.98; Found 580.8
(M+H).
Example 115
2-[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]di-
azepin-4-yl]-3-naphthalen-2-yl-propionic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.77 (s, 0.7H), 10.42
(s, 0.3H), 7.87 7.84 (m, 1.0H), 7.82 7.68 (m, 3.0 Hz), 7.66 7.62
(m, 0.7H), 7.58 (bs, 0.3H), 7.55 (d, J=2.0 Hz, 1.0H), 7.51 7.36 (m,
3.0H), 7.20 7.07 (m, 3.0H), 6.92 (bs, 1.0H), 6.56 6.52 (m, 1.0H),
5.80 (bs, 0.7H), 5.58 (bs, 0.7H), 5.44 (bs, 0.3H), 5.38 (bs, 0.3H)
3.62 3.08 (m, 2.0H). Mass spectrum (LCMS, ESI pos.) Calcd. For
C.sub.28H.sub.20ClIN.sub.2O.sub.4: 610.02 Found: 610.94 (M+H).
Example 116
2-[7-Iodo-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro-benzo-
[e][1,4]diazepin-4-yl]-3-naphthalen-2-yl-propionic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.77 (s, 0.7H), 10.44
(s, 0.3H), 7.92 7.55 (m, 5.0H), 7.56 7.36 (m, 4.0H), 7.31 7.19 (bs,
1.0H), 7.12 6.96 (m, 2.0H), 6.93 6.82 (m, 1.0H), 6.58 6.46 (m,
1.0H), 5.80 (bs, 0.7H), 5.67 5.57 (m, 0.7H), 5.49 (s, 0.3H), 5.43
5.35 (m, 0.3H), 3.71 3.52 (m, 1.0H), 3.21 3.08 (m, 1.0H). Mass
spectrum (LCMS, ESI pos.) Calcd. For
C.sub.29H.sub.20F.sub.3IN.sub.2O.sub.5: 660.04. Found: 660.98
(M+H).
Example 117
2-[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]di-
azepin-4-yl]-3-naphthalen-1-yl-propionic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.94 (s, 0.7H), 10.39
(s, 0.3H), 8.32 (d, J=8.8 Hz, 0.7H), 8.27 8.15 (m, 0.3H), 7.97 7.83
(m, 1.0H), 7.84 7.73 (m, 0.3H), 7.73 7.65 (m, 0.7H), 7.62 7.44 (m,
3.0H), 7.40 7.23 (m, 3.0H), 7.22 7.07 (m, 3.0H), 6.64 6.54 (m,
1.0H), 5.87 (bs, 1.0H), 5.62 (bs, 1.0H), 5.36 (bs, 0.6H), 5.20 (bs,
0.4H), 3.89 3.52 (m, 2.0H). Mass spectrum (LCMS, ESI pos.) Calcd.
For C.sub.28H.sub.20ClIN.sub.2O.sub.4: 610.02. Found: 610.92
(M+H).
Example 118
2-[7-Iodo-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro-benzo-
[e][1,4]diazepin-4-yl]-3-naphthalen-1-yl-propionic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.94 (s, 0.7H), 10.40
(s, 0.3H), 8.34 (d, J=8.4 Hz, 0.7H), 8.21 (bs, 0.3H), 7.88 (d,
J=8.0 Hz, 1.0H), 7.78 (d, J=7.2 Hz, 0.3H), 7.69 (d, J=8.4 Hz,
0.7H), 7.72 7.68 (m, 5.0H), 7.67 7.22 (m, 4.0H), 7.07 (d, J=8.4 Hz,
1.0H), 7.04 7.00 (m, 0.3H), 6.58 (d, J=8.8 Hz, 0.7H), 5.90 (bs,
0.7H), 5.70 5.63 (m, 0.7H), 5.46 5.37 (m, 0.3H), 5.26 5.16 (m,
0.3H), 3.97 3.60 (m, 2.0H). Mass spectrum (LCMS, ESI pos.) Calcd.
For C.sub.29H.sub.20F.sub.3IN.sub.2O.sub.5: 660.04; Found:
660.99(M+H).
Example 119
[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diaz-
epin-4-yl]-(4-fluoro-phenyl)-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.62 (s, 0.6H), 10.50
(s, 0.4H), 7.80 (d, J=2 Hz, 0.6H), 7.72 (d, J=2.4 Hz, 0.4H), 7.58
7.47 (m, 2.0H), 7.44 7.32 (m, 1.0H), 7.25 7.03 (m, 4.0H), 6.87 6.75
(m, 1.0H), 6.64 (d, J=8.4 Hz, 0.6H), 6.55 (d, J=8.4 Hz, 0.4H), 6.29
(d, J=6 Hz, 1.0H), 5.80 (s, 0.6H), 5.76 (s, 0.4H), 5.22 (1.0H).
Mass spectrum (LCMS, ESI pos.) Calcd. For
C.sub.23H.sub.15ClFIN.sub.2O.sub.4: 563.97; Found: 564.84
(M+H).
Example 120
(4-Fluoro-phenyl)-[7-iodo-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5--
tetrahydrobenzo[e][1,4]diazepin-4-yl]-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.63 (s, 0.7H), 10.48
(s, 0.3H), 7.75 (d, J=2 Hz, 0.7H), 7.67 (d, J=2 Hz, 0.3H), 7.59
7.46 (m, 2.3H), 7.43 7.36 (m, 0.7H), 7.29 (d, J=8.4 Hz, 0.7H), 7.16
7.06 (m, 2.3H), 7.03 6.97 (d, J=8.4 Hz, 1.0H), 6.93 6.87 (d, J=8.4
Hz, 1.0H), 6.63 (d, J=8.8 Hz, 0.7H), 6.53 (d, J=8.8 Hz, 0.3H), 6.32
(s, 0.3H), 6.28 (s, 0.7H), 5.83 (s, 1.0H), 5.76 (s, 0.3H), 5.25 (s,
0.7H). Mass spectrum (LCMS, ESI pos.) Calcd. For
C.sub.24H.sub.15F.sub.4IN.sub.2O.sub.5: 614.00; Found:
614.94(M+H).
Example 121
2-[7-Iodo-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5tetrahydrobenzo[e-
][1,4]diazepin-4-yl]-3-(4-iodo-phenyl)-propionic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.72 (s, 0.8H), 10.49
(s, 0.2H), 7.68 (s, 0.4H), 7.60 7.49 (m, 2.6H), 7.49 7.43 (m,
0.1H), 7.27 7.20 (m, 3.0H), 7.11 7.04 (m, 3.0H), 7.00 (d, J=8 Hz,
0.2H), 6.53 (d, J=8.8 Hz, 0.8H), 5.73 (s, 1.0H), 5.56 5.45 (m,
0.8H), 5.40 (s, 0.2H), 2.95 2.84 (m, 2.0H). Mass spectrum (LCMS,
ESI pos.) Calcd. For C.sub.25H.sub.17F.sub.3I.sub.2N.sub.2O.sub.5:
735.92. Found: 736.83 (M+H).
Example 122
3-(4-Bromo-phenyl)-2-[7-iodo-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3-
,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-propionic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.70 (s, 0.4H), 10.47
(s, 0.6H), 7.69 (d, J=2 Hz, 0.6H), 7.48 (d, J=2 Hz, 0.4H), 7.51
7.43 (m, 1.0H), 7.39 7.33 (m, 2.0H), 7.29 7.12 (m, 3.0H), 7.09 6.99
(m, 2.0H), 6.60 6.50 (m, 1.0H), 5.76 (s, 1.0H), 5.53 (bs, 0.6H),
5.39 (s, 0.4H), 5.10 (bs, 1.0H), 3.17 (d, J=5.12 Hz, 2.0H). Mass
spectrum (LCMS, ESI pos.) Calcd. For
C.sub.25H.sub.17BrF.sub.3IN.sub.2O.sub.5: 687.93. Found: 688.80
(M+H).
Example 123
3-(4-Bromo-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahy-
dro-benzo[e][1,4]diazepin-4-yl]-propionic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.73 (s, 0.6H), 10.50
(s, 0.4H), 7.73 (d, J=2 Hz, 0.4H), 7.60 (d, J=2 Hz, 0.6H), 7.55
7.45 (m, 1.0H), 7.41 7.32 (m, 2.0H), 7.25 7.03 (m, 6.0H), 6.55 (d,
J=8.4 Hz, 1.0H), 5.70 (s, 0.6H), 5.55 5.46 (m, 0.6H), 5.35 (s,
0.4H), 5.10 (bs, 0.4H), 3.20 2.84 (m, 2.0H). Mass spectrum (LCMS,
ESI pos.) Calcd. For C.sub.24H.sub.17BrClIN.sub.2O.sub.4: 637.91.
Found: 638.82(M+H).
Example 124
2-[7-Iodo-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro-benzo-
[e][1,4]diazepin-4-yl]-3-thiophen-2-yl-propionic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.83 (s, 0.7H), 10.59
(s, 0.3H), 7.73 (bs, 0.3H), 7.70 7.66 (m, 0.7H), 7.60 7.55 (m,
0.3H), 7.51 (dd, J=2.0 Hz, 8.0 Hz, 0.7H), 7.32 (d, J=5.2 Hz, 0.3H),
7.30 7.25 (m, 1.7H), 7.19 7.04 (m, 4.0H), 6.92 6.84 (m, 2.0H), 5.69
(s, 0.7H), 5.48 5.41 (m, 1.0H), 5.19 (bs, 0.3H), 3.56 3.15 (m,
2.0H). Mass spectrum (LCMS, ESI pos.) Calcd. For
C.sub.23H.sub.16F.sub.3IN.sub.2O.sub.5S: 615.98. Found: 616.75
(M+H).
Example 125
[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diaz-
epin-4-yl]-(4-trifluoromethyl-phenyl)-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.61 (s, 0.6H), 10.58
(s, 0.4H), 7.80 (d, J=2.4 Hz, 0.6H), 7.73 (d, J=2.0 Hz, 0.4H), 7.72
7.62 (m, 3.0H), 7.58 7.50 (m, 2.0H), 7.18 (s, 2.0H), 7.06 (d, J=8.4
Hz, 1.0H), 6.88 6.82 (m, 1.0H), 6.63 (d, J=8.4 Hz, 0.6H), 6.53 (d,
J=8.4 Hz, 0.4H), 6.37 (s, 0.4H), 6.27 (s, 0.6H), 5.76 (s, 0.4H),
5.28 (s, 0.6H). Mass spectrum (LCMS, ESI pos.) Calcd. For
C.sub.24H.sub.15ClF.sub.3N.sub.2O.sub.4: 613.97. Found: 614.86
(M+H).
Example 126
2-[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]di-
azepin-4-yl]-3-thiophen-2-yl-propionic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.85 (s, 0.7H), 10.59
(s, 0.3H), 7.75 7.71 (m, 1.0H), 7.70 7.66 (m, 1.0H), 7.60 7.49 (m,
1.0H), 7.32 (d, J=5.2 Hz, 0.3H), 7.30 7.25 (m, 0.7H), 7.19 7.03 (m,
3.0H), 6.93 6.84 (m, 1.0H), 6.78 (d, J=8.0 Hz, 0.7H), 6.65 (d,
J=8.8 Hz, 0.3H), 6.58 (d, J=8.4 Hz, 1.0H), 5.57 (s, 0.7H), 5.53
5.47 (m, 0.7H), 5.41 (s, 0.3H), 5.28 5.21 (bs, 0.3H), 3.62 3.54 (m,
2.0H). Mass spectrum (LCMS, ESI pos.) Calcd. For
C.sub.22H.sub.16ClIN.sub.2O.sub.4S: 565.96. Found: 566.90 (M+H),
591.32 (M+Na).
Example 127
[7-Iodo-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro
benzo[e][1,4]diazepin-4-yl]-(4-trifluoromethyl-phenyl)-acetic
acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.66 (s, 0.8H), 10.57
(s, 0.2H), 7.79 7.74 (d, J=2.0 Hz, 1.0H), 7.73 7.61 (m, 4.0H), 7.56
7.49 (dd, J=1.6 Hz, 8.4 Hz, 1.0H), 7.03 6.92 (m, 3.0H), 6.62 (d,
J=8.4 Hz, 2.0H), 6.27 (bs, 1.0H), 5.93 (s, 0.4H), 5.38 (s, 0.6H).
Mass spectrum (LCMS, ESI pos.) Calcd. For
C.sub.25H.sub.15F.sub.6IN.sub.2O.sub.5: 663.99. Found 664.89
(M+H).
Example 128
(4-Chloro-phenyl)-[7-iodo-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5--
tetrahydrobenzo[e][1,4]diazepin-4-yl]-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.53 (s, 0.6H), 10.49
(s, 0.4H), 7.74 (d, J=2.3 Hz, 0.6H), 7.66 (d, J=2.1 Hz, 0.4H), 7.53
7.47 (m, 2.0H), 7.38 7.32 (m, 2.0H), 7.28 (d, J=8.8 Hz, 1.0H), 7.09
(d, J=8.8 Hz, 1.0H), 7.05 6.88 (m, 3.0H), 6.62 (d, J=8.8 Hz, 0.6H),
6.53 (d, J=9.6 Hz, 0.4H), 6.28 (s, 0.4H), 6.20 (s, 0.6H), 5.89 (s,
0.4H), 5.23 (s, 0.6H). Mass spectrum (LCMS, ESI pos.) Calcd. For
C.sub.24H.sub.15ClF.sub.3IN.sub.2O.sub.5: 629.97. Found 630.89
(M+H).
Example 129
(4-Chloro-phenyl)-[7-iodo-2,5-dioxo-3-(4-trifluoromethyl-phenyl)-1,2,3,5-t-
etrahydrobenzo[e][1,4]diazepin-4-yl]-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.60 (s, 0.6H), 10.53
(s, 0.4H), 7.78 (d, J=2.0 Hz, 0.6H), 7.70 (d, J=2.0 Hz, 0.4H), 7.56
7.45 (m, 3.0H), 7.43 7.31 (m, 4.0H), 7.10 7.00 (m, 1.0H), 6.62 (d,
J=8.8 Hz, 1.0H), 6.52 (d, J=8.8 Hz, 0.6H), 6.31 (s, 0.4H), 6.24 (s,
0.6H), 6.02 5.96 (m, 0.4H), 5.31 5.25 (m, 1.0H). Mass spectrum
(LCMS, ESI pos.) Calcd. For
C.sub.24H.sub.15ClF.sub.3IN.sub.2O.sub.4: 613.97. Found
614.86(M+H).
Example 130
[3-(4-Bromo-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diaze-
pin-4-yl]-(4-chloro-phenyl)-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.60 (s, 0.7H), 10.48
(s, 0.3H), 7.80 (d, J=2.4 Hz, 0.7H), 7.72 (d, J=2.0 Hz, 0.3H), 7.56
7.45 (m, 2.0H), 7.40 7.27 (m, 3.0H), 7.25 7.18 (m, 1.0H), 7.15 7.09
(m, 1.0H), 6.77 (m, 1.0H), 6.63 (d, J=8.8 Hz, 0.3H), 6.54 (d, J=4.8
Hz, 0.7H), 6.27 (s, 0.3H), 6.22 (s, 0.7H), 5.84 (bs, 1.0H), 5.16
(s, 1.0H). Mass spectrum (LCMS, ESI pos.) Calcd. For
C.sub.23H.sub.15BrClIN.sub.2O.sub.4: 623.89. Found 626.77
(M+H).
Example 131
[3-(4-Bromo-phenyl)-2,5-dioxo-7-phenyl-1,2,3,5-tetrahydro-benzo[e][1,4]dia-
zepin-4-yl]-(4-chloro-phenyl)-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.67 (s, 0.7H), 10.53
(s, 0.3H), 7.82 (d, J=2.0 Hz, 0.7H), 7.74 (d, J=2.0 Hz, 0.3H), 7.58
7.49 (m, 4.0H), 7.47 7.40 (m, 3.0H), 7.38 7.30 (m, 3.0H), 7.29 7.24
(m, 1.0H), 7.21 7.14 (m, 2.0H), 6.91 (d, J=8.4 Hz, 1.0H), 6.86 6.79
(m, 1.0H), 6.40 (s, 0.3H), 6.34 (s, 0.7H), 5.81 (s, 0.3H), 5.26 (s,
0.7H). Mass spectrum (LCMS, ESI pos.) Calcd. For
C.sub.29H.sub.20BrClN.sub.2O.sub.4: 574.03. Found 574.90 (M+H).
Example 132
(4-Chloro-phenyl)-[2,5-dioxo-7-phenyl-3-(4-trifluoromethyl-phenyl)-1,2,3,5-
-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.69 (s, 0.5H), 10.55
(s, 0.5H), 7.79 7.68 (m, 2.0H), 7.58 7.29 (m, 11.0H), 7.16 (bs,
2.0H), 6.94 6.85 (m, 0.5H), 6.80 (d, J=8.4 Hz, 0.5H), 6.40 (bs,
0.5H), 6.30 (bs, 0.5H), 5.95 (bs, 0.5H), 5.33 (bs, 0.5H). Mass
spectrum (LCMS, ESI pos.) Calcd. For
C.sub.30H.sub.20ClF.sub.3N.sub.2O.sub.4: 564.11. Found 565.02
(M+H).
Example 133
(4-Chloro-phenyl)-[2,5-dioxo-7-phenyl-3-(4-trifluoromethoxy-phenyl)-1,2,3,-
5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.63 (s, 0.4H), 10.50
(s, 0.6H), 7.73 (d, J=2.4 Hz, 0.4H), 7.66 (d, J=2.4 Hz, 0.6H), 7.60
7.28 (m, 11.0H), 7.05 (d, J=8.4 Hz, 2.0H), 6.99 (s, 1.0H), 6.90 (d,
J=8.0 Hz, 0.6H), 6.80 (d, J=8.4 Hz, 0.4H), 6.40 (bs, 0.6H), 6.29
(bs, 0.4H), 5.87 (bs, 0.6H), 5.30 (bs, 0.4H). Mass spectrum (LCMS,
ESI pos.) Calcd. For C.sub.30H.sub.20ClF.sub.3N.sub.2O.sub.5:
580.10. Found 581.00 (M+H).
Example 134
(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-2,5-dioxo-7-phenyl-1,2,3,5-tetrahyd-
ro-benzo[e][1,4]diazepin-4-yl]-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.62 (s, 0.4H), 10.51
(s, 0.6H), 7.81 (d, J=1.6 Hz, 0.4H), 7.73 (d, J=2.4 Hz, 0.6H), 7.59
7.48 (m, 4.0H), 7.47 7.30 (m, 5.0H), 7.23 (d, J=8.4 Hz, 1.0H), 7.13
(d, J=8.4 Hz, 2.0H), 7.06 (d, J=8.8 Hz, 2.0H), 6.91 (d, J=8.0 Hz,
1.0H), 6.82 (d, J=8.4 Hz, 1.0H), 6.39 (bs, 0.6H), 6.33 (bs, 0.4H),
5.84 (bs, 0.4H), 5.27 (bs, 0.6H). Mass spectrum (LCMS, ESI pos.)
Calcd. For C.sub.29H.sub.20Cl.sub.2N.sub.2O.sub.4: 530.08. Found
531.01(M+H).
Example 135
[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diaz-
epin-4-yl]-thiophen-2-yl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.62 (s, 0.8H), 10.52
(s, 0.2H), 7.80 (d, J=2.4 Hz, 0.8H), 7.73 (d, J=2.4 Hz, 0.2H), 7.56
7.51 (m, 1.0H), 7.37 (d, J=8.4 Hz, 1.0H), 7.19 7.15 (m, 1.0H), 7.10
(d, J=8.6 Hz, 2.0H), 6.95 6.91 (m, 1.0H), 6.80 (d, J=8.4 Hz, 2.0H),
6.65 (d, J=8.6 Hz, 0.8H), 6.58 (d, J=8.4 Hz, 0.2H), 6.44 (bs,
0.6H), 5.85 (bs, 0.4H), 5.50 (bs, 1.0H). Mass spectrum (LCMS, ESI
pos.) Calcd. For C.sub.21H.sub.14ClIN.sub.2O.sub.4S: 551.94. Found
552.83 (M+H).
Example 136
[7-Iodo-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro-benzo[e-
][1,4]diazepin-4-yl]-thiophen-2-yl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.65 (s, 0.8H), 10.52
(s, 0.2H), 7.74 (d, 2.0 Hz, 0.8H), 7.68 (d, J=2.0 Hz, 0.2H), 7.55
7.49 (m, 1.0H), 7.42 7.37 (m, 1.0H), 7.28 (d, J=8.4 Hz, 0.2H), 7.20
(d, J=2.8 Hz, 0.8H), 7.13 6.99 (m, 2.0H), 6.96 6.87 (m, 3.0H), 6.64
(d, J=8.8 Hz, 0.8H), 6.56 (d, J=8.8 Hz, 0.2H), 6.44 (bs, 0.8H),
5.88 (bs, 0.2H), 5.55 (bs, 1.0H). Mass spectrum (LCMS, ESI pos.)
Calcd. For C.sub.22H.sub.14F.sub.3N.sub.2O.sub.5S: 601.96. Found
602.81(M+H).
Example 137
(3-Biphenyl-4-yl-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-
-4-yl)-(4-chloro-phenyl)-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.63 (s, 0.7H), 10.52
(s, 0.3H), 7.82 (d, J=2.0 Hz, 0.7H), 7.74 (d, J=2.4 Hz, 0.3H), 7.57
7.22 (m, 12.0H), 6.86 (d, J=7.6 Hz, 2.0H), 6.66 (d, J=7.6 Hz,
0.7H), 6.56 (d, J=8.8 Hz, 0.3H), 6.33 (bs, 0.7H), 5.95 (bs, 0.3H),
5.29 (bs, 1.0H). Mass spectrum (LCMS, ESI pos.) Calcd. For
C.sub.29H.sub.20ClIN.sub.2O.sub.4: 622.02. Found 622.91 (M+H).
Example 138
[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diaz-
epin-4-yl]-(4-ethyl-phenyl)-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.68 (s, 0.8H), 10.51
(s, 0.2H), 7.79 (d, J=2.0 Hz, 0.8H), 7.73 (d, J=2.0 Hz, 0.2H), 7.56
7.49 (m, 1.01H), 7.39 (d, J=8.0 Hz, 2.0H), 7.29 7.15 (m, 1.0H),
7.12 (d, J=8.0 Hz, 2.0H), 7.06 (d, J=8.4 Hz, 1.0H), 6.77 (d, J=8.0
Hz, 2.0H), 6.64 (d, J=8.4 Hz, 0.8H), 6.55 (d, J=8.8 Hz, 0.2H), 6.30
(bs, 1.0H), 5.82 (bs, 0.2H), 5.21 (bs, 0.8H), 2.62 2.51 (m, 2.0H),
1.21 1.14 (m, 3.0H). Mass spectrum (LCMS, ESI pos.) Calcd. For
C.sub.25H.sub.20ClIN.sub.2O.sub.4: 574.02. Found 574.94 (M+H).
Example 139
[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diaz-
epin-4-yl]-(3,4-dichloro-phenyl)-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.70 (s, 0.6H), 10.64
(s, 0.4H), 7.79 (d, J=2.0 Hz, 1.0H), 7.81 7.78 (m, 1.0H), 7.61 7.46
(m, 2.0H), 7.40 7.31 (m, 1.0H), 7.18 (s, 1.0H), 7.13 (d, J=8.4 Hz,
1.0H), 7.04 7.00 (m, 1.0H), 6.63 (d, J=8.4 Hz, 1.0H), 6.56 (d,
J=8.8 Hz, 0.6H), 6.29 (bs, 0.4H), 6.12 (bs, 0.6H), 5.80 (bs, 0.4H),
5.32 (bs, 1.0H). Mass spectrum (LCMS, ESI pos.) Calcd. For
C.sub.23H.sub.14Cl.sub.3IN.sub.2O.sub.4: 613.91. Found 614.84
(M+H).
Example 140
(2-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-
-benzo[e][1,4]diazepin-4-yl]-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.61 (s, 0.2H), 10.55
(s, 0.8H), 7.77 (d, J=2.4 Hz, 1.0H), 7.60 7.49 (m, 2.0H), 7.44 7.30
(m, 4.0H), 7.16 (d, J=8.8 Hz, 1.0H), 7.11 (d, J=8.4 Hz, 0.2H), 6.89
(d, J=8.0 Hz, 0.8H), 6.61 (d, J=8.8 Hz, 1.0H), 6.55 (d, J=8.8 Hz,
1.0H), 6.29 (bs, 1.0H), 5.23 (bs, 0.8H), 5.10 (bs, 0.2H). Mass
spectrum (LCMS, ESI pos.) Calcd. For
C.sub.23H.sub.15Cl.sub.2IN.sub.2O.sub.4: 579.95. Found 580.92
(M+H).
Example 141
(4-tert-Butyl-phenyl)-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrah-
ydro-benzo[e][1,4]diazepin-4-yl]-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.62 (s, 0.7H), 10.55
(s, 0.3H), 7.77 (d, J=2.0 Hz, 0.7H), 7.75 7.67 (m, 0.3H), 7.55 7.48
(m, 1.0H), 7.39 (d, J=8.4 Hz, 2.0H), 7.29 (d, J=8.4 Hz, 2.0H), 7.25
7.14 (m, 1.0H), 7.02 (d, J=8.0 Hz, 2.0H), 6.92 (d, J=8.0 Hz, 0.3H),
6.73 6.62 (m, 3.0H), 6.54 (d, J=8.4 Hz, 0.7H), 6.27 (s, 1.0H), 5.92
(bs, 0.3H), 5.27 (bs, 0.7H), 1.27 (s, 1.0H), 1.20 (s, 9.0H). Mass
spectrum (LCMS, ESI pos.) Calcd. For
C.sub.27H.sub.24ClIN.sub.2O.sub.4: 602.05. Found 602.99 (M+H).
Example 142
[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diaz-
epin-4-yl]-(4-isopropyl-phenyl)-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.69 (s, 0.8H), 10.54
(s, 0.2H), 7.79 (d, J=2.0 Hz, 0.8H), 7.73 (d, J=2.0 Hz, 0.2H), 7.57
7.50 (m, 1.0H), 7.39 (d, J=8.0 Hz, 2.0H), 7.27 (d, J=8.0 Hz, 0.8H),
7.21 (d, J=8.4 Hz, 0.2H), 7.14 (d, J=8.0 Hz, 2.0H), 7.03 (d, J=8.4
Hz, 2.0H), 6.72 (d, J=8.8 Hz, 1.0H), 6.65 (d, J=8.8 Hz, 1.0H), 6.54
(d, J=8.8 Hz, 0.2H), 6.30 (bs, 0.8H), 5.86 (bs, 0.2H), 5.27 (bs,
0.8H), 2.88 2.76 (m, 1.0H), 1.18 (d, J=8.8 Hz, 1.2H), 1.11 (d,
J=6.8 Hz, 6.0H). Mass spectrum (LCMS, ESI pos.) Calcd. For
C.sub.26H.sub.22ClIN.sub.2O.sub.4: 588.03. Found 588.95 (M+H).
Example 143
(3-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-
-benzo[e][1,4]diazepin-4-yl]-acetic acid
.sup.1H NMR (400 MHz, DMSO-d6): .delta. 10.69 (s, 0.7H), 10.60 (s,
0.3H), 7.80 (d, J=2.0 Hz, 0.7H), 7.73 (d, J=2.4 Hz 0.3H), 7.57 7.50
(m, 2.0H), 7.49 7.44 (m, 0.7H), 7.41 (s, 0.3H), 7.35 7.29 (m,
3.0H), 7.18 (s, 1.0H), 6.92 (d, J=8.0 Hz, 2.0H), 6.63 (d, J=8.8 Hz,
0.7H), 6.56 (d, J=8.4 Hz, 0.3H), 6.31 (bs, 0.3H), 6.23 (bs, 0.7H),
5.84 (bs, 0.3H), 5.26 (bs, 0.7H). Mass spectrum (LCMS, ESI pos.)
Calcd. For C.sub.23H.sub.15Cl.sub.2IN.sub.2O.sub.4: 579.95. Found
581.00 (M+H).
Example 144
[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diaz-
epin-4-yl]-(4-trifluoromethoxy-phenyl)-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.72 (s, 0.8H), 10.59
(s, 0.2H), 7.80 (d, J=2.0 Hz, 0.8H), 7.74 (d, J=2.0 Hz, 0.2H), 7.61
(d, J=8.8 Hz, 2.0H), 7.57 7.48 (m, 2.0H), 7.28 (d, J=8.4 Hz, 2.0H),
7.18 (s, 1.0H), 7.07 (d, J=8.4 Hz, 1.0H), 6.85 6.12 (m, 1.0H), 6.65
(d, J=8.4 Hz, 0.8H), 6.55 (d, J=8.4 Hz, 0.2H), 6.35 (bs, 0.2H),
6.31 (bs, 0.8H), 5.77 (bs, 0.2H), 5.31 (bs, 0.8H). Mass spectrum
(LCMS, ESI pos.) Calcd. For
C.sub.24H.sub.15ClF.sub.3IN.sub.2O.sub.5: 629.97. Found 630.95
(M+H).
Example 145
(4-Bromo-phenyl)-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro--
benzo[e][1,4]diazepin-4-yl]-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.69 (s, 0.7H), 10.56
(s, 0.3H), 7.79 (d, J=2.0 Hz, 0.7H), 7.73 (d, J=2.0 Hz, 0.3H), 7.58
7.41(m, 5.0H), 7.32 (d, J=8.4 Hz, 1.0H), 7.23 (s, 1.0H), 7.11 (d,
J=8.8 Hz, 1.0H), 6.94 6.85 (m, 1.0H), 6.64 (d, J=8.4 Hz, 0.7H),
6.55 (d, J=8.0 Hz, 0.3H), 6.29 (bs, 0.3H), 6.23 (bs, 0.7H), 5.78
(bs, 0.3H), 5.23 (bs, 0.7H). Mass spectrum (LCMS, ESI pos.) Calcd.
For C.sub.23H.sub.15BrClIN.sub.2O.sub.4: 623.89. Found 624.90
(M+H).
Example 146
[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diaz-
epin-4-yl]-(3-hydroxy-phenyl)-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.48 (s, 1.0H), 9.50,
(s, 1.0H), 7.78 (d, J=2.0 Hz, 1.0H), 7.54 (dd, J=2.0 Hz, 8.0 Hz,
1.0H), 7.08 (d, J=8.4 Hz, 3.0H), 6.91 (s, 2.0H), 6.84 6.76 (m,
2.0H), 6.69 6.59 (m, 2.0H), 6.26 (bs, 1.0H), 5.24 (bs, 1.0H). Mass
spectrum (LCMS, ESI pos.) Calcd. For
C.sub.23H.sub.16ClIN.sub.2O.sub.5: 561.98. Found 562.89 (M+H).
Example 147
[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diaz-
epin-4-yl]-(4-hydroxy-phenyl)-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.58 (s, 0.7H), 10.43
(s, 0.3H), 9.43 (s, 0.7H), 9.38 (s, 0.3H) 7.76 (d, J=2.4 Hz, 1.0H),
7.70 (d, J=1.6 Hz, 0.3H), 7.50 (m, 0.7H), 7.25 (d, J=8.4 Hz, 2.0H),
7.23 7.11 (m, 3.0H), 7.07 (d, J=2.4 Hz, 1.0H), 6.83 6.76 (m, 1.0H),
6.68 6.60 (m, 2.0H), 6.22 (bs, 1.0H), 6.17 (bs, 0.3H), 5.14 (bs,
0.7H). Mass spectrum (LCMS, ESI pos.) Calcd. For
C.sub.23H.sub.16ClIN.sub.2O.sub.5: 561.98. Found 562.80 (M+H).
Example 148
(4-Chloro-phenyl)-[3-(4-chloro-3-trifluoromethyl-phenyl)-7-iodo-2,5-dioxo--
1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.80 (s, 0.6H), 10.63
(s, 0.4H), 7.76 7.69 (m, 1.0H), 7.61 7.44 (m, 3.0H), 7.40 (s,
1.0H), 7.36 7.21 (m, 1.0H), 7.17 (d, J=8.0 Hz, 1.0H), 6.67 6.51 (m,
2.0H), 6.38 6.19 (m, 1.0H), 5.63 (bs, 0.4H), 5.50 (bs, 0.6H), 5.17
(bs, 1.0H). Mass spectrum (LCMS, ESI pos.) Calcd. For
C.sub.24H.sub.14Cl.sub.2F.sub.3IN.sub.2O.sub.4: 647.93. Found
648.91(M+H).
Example 149
[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diaz-
epin-4-yl]-cyclohexyl-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.99 (s, 1.0H), 7.74
(d, J=1.6 Hz, 1.0H), 7.57 (dd, J=2.0 Hz, 8.4 Hz, 1.0H), 7.22 (d,
J=8.8 Hz, 2.0H), 6.96 (d, J=8.4 Hz, 2.0H), 6.62 (d, J=8.8 Hz,
1.0H), 5.90 (bs, 1.0H), 5.17 5.10 (m, 1.0H), 1.89 0.87 (m, 1.0H).
Mass spectrum (LCMS, ESI pos.) Calcd. For
C.sub.23H.sub.22ClIN.sub.2O.sub.4: 552.03. Found 552.90 (M+H).
Example 150
(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-iodo-8-methyl-2,5-dioxo-1,2,3,5-t-
etrahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.63 (s, 0.4H), 10.51
(s, 0.6H), 7.93 (s, 0.4H), 7.85 (s, 0.6H), 7.50 (d, J=8.8 Hz,
1.0H), 7.41 7.31 (m, 3.0H), 7.18 (s, 2.0H), 7.09 (d, J=8.8 Hz,
1.0H), 6.86 6.81 (m, 0.6H), 6.77 (s, 0.4H), 6.68 (s, 1.0H), 6.35
6.27 (m, 1.0H), 5.78 (bs, 0.6H), 5.25 (bs, 0.4H) 2.18 (s, 1.8H),
2.17 (s, 1.2H). Mass spectrum (LCMS, ESI pos.) Calcd. For
C.sub.24H.sub.17Cl.sub.2IN.sub.2O.sub.4: 593.96 (M+H). Found
594.89.
Example 151
[3-(4-Chloro-phenyl)-7,8-difluoro-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,-
4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H -NMR (400 MHz, DMSO-d.sub.6): .delta. 7.6 7.7 (m, 2H), 7.4
7.5 (m, 1H), 7.2 7.4 (m, 4H), 6.9 7.0 (m, 2H), 6.6 6.8 (m, 4H), 5.7
(s, 0.13H), 5.4 (s, 0.87H). Mass spectrum (LCMS, ESI pos) Calcd.
for C.sub.23H.sub.15ClF.sub.2N.sub.2O.sub.4: 456.1; Found: 457.0
(M+H).
Example 152
[7,8-Difluoro-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro-b-
enzo[e][1,4]diazepin-4-y 1]-phenyl-acetic acid
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 7.6 (m, 2H), 7.2 7.5
(m, 5H), 6.6 6.9 (m, 6H), 5.8 (s, 0.1H), 5.4 (s, 0.9H). (LCMS, ESI
pos) Calcd. for C.sub.24H.sub.15F.sub.5N.sub.2O.sub.5: 506.1;
Found: 507.1 (M +H).
Example 153
[3-(4-Chloro-phenyl)-7-fluoro-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]di-
azepin-4-yl]-phenyl-acetic acid
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 7.6 7.7 (m, 2H), 7.2
7.4 (m, 5H), 6.9 7.1 (m, 2H), 6.6 6.9 (m, 6H), 5.7 (m, 0.1H), 5.4
5.5 (s, 0.9H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.23H.sub.16ClFN.sub.2O.sub.4: 438.1; Found: 439.0 (M+H).
Example 154
[7-Fluoro-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro-benzo-
[e][1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 7.6 7.7 (m, 2H), 7.4
7.5 (m, 1H), 7.2 7.4 (m, 5H), 6.9 7.0 (m, 2H), 6.6 6.9 (m, 7H), 5.7
(s, 0.2H), 5.5 (s, 0.8H). ). Mass spectrum (LCMS, ESI pos) Calcd.
for C.sub.24H.sub.16F.sub.4N.sub.2O.sub.5: 488.1; Found: 489.1
(M+H).
Example 155
[7-Acetylamino-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1-
,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 7.4 7.9 (m, 5H), 7.0
7.3 (m, 3H), 6.6 6.9 (m, 7H), 5.4 5.8 (m, 1H), 1.9 2.2 (s, 3H).
Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.25H.sub.20ClN.sub.3O.sub.5: 477.1; Found: 478.0 (M+H).
Example 156
[7-Acetylamino-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro--
benzo[e][1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 7.6 7.9 (m, 3H), 7.2
7.5 (m, 5H), 6.6 6.9 (m, 6H), 5.7 (br s, 1H), 1.9 2.2 (s, 1H).
(LCMS, ESI pos) Calcd. for C.sub.26H.sub.20F.sub.3N.sub.3O.sub.6:
527.1; Found: 528.1 (M+H).
Example 157
[3-(4-Chloro-phenyl)-7-(3-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benz-
o[e][1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 7.8 7.9 (s, 1H), 7.6
7.7 (m, 2H), 7.2 7.5 (m, 8H), 6.8 6.9 (m, 3H), 6.7 6.8 (m, 3H), 5.4
(s, 1H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.29H.sub.20Cl.sub.2N.sub.2O.sub.4: 530.1; Found: 531.0
(M+H).
Example 158
[3-(4-Chloro-phenyl)-7-(4-methyl-thiophen-2-yl)-2,5-dioxo-1,2,3,5-tetrahyd-
ro-benzo[e][1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 7.8 (s, 1H), 7.6 7.7
(s, 1H), 7.4 7.5 (m, 5H), 7.2 7.4 (m, 2H), 6.6 6.9 (m, 5H), 5.7 (s,
0.4H), 5.4 5.5 (s, 0.6H), 2.2 (3H, s). Mass spectrum (LCMS, ESI
pos) Calcd. for C.sub.28H.sub.21ClN.sub.2O.sub.4S: 516.1; Found:
517.0 (M+H).
Example 159
[3-(4-Chloro-phenyl)-2,5-dioxo-7-thiophen-3-yl-1,2,3,5-tetrahydro-benzo[e]-
[1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 7.9 (s, 1H), 7.6 (s,
1H), 7.4 7.55 (m, 4H), 7.2 7.4 (m, 5H), 7.0 7.1 (m, 1H), 6.8 6.9
(m, 2H), 6.7 6.8 (m, 2H), 5.7 (s, 0.5H), 5.4 (s, 0.5H). Mass
spectrum (LCMS, ESI pos) Calcd. for
C.sub.27H.sub.19ClN.sub.2O.sub.4S: 502.1; Found: 503.0 (M+H).
Example 160
[3-(4-Chloro-phenyl)-7-furan-3-yl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,-
4]diazepin-4-yl]-phenyl-acetic acid methyl ester
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 7.9 (s, 1H), 7.8 (s,
1H), 7.4 7.7 (m, 8H), 7.0 7.3 (m, 3H), 6.7 6.9 (m, 3H), 5.3 (s,
0.4H), 5.2 (s, 0.6H,), 3.8 (s, 3H). Mass spectrum (LCMS, ESI pos)
Calcd. for C.sub.28H.sub.21ClN.sub.2O.sub.5: 500.0; Found: 501.0
(M+H).
Example 161
[3-(4-Chloro-phenyl)-7-furan-3-yl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,-
4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 7.8 7.9 (m, 2H), 7.6
7.7 (m, 1H), 7.2 7.5 (m, 7H), 7.0 7.1 (m, 1H), 6.6 6.9 (m, 5H), 5.7
(s, 0.4H), 5.5 (m, 0.6H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.27H.sub.19ClN.sub.2O.sub.5: 486.1; Found: 487.0 (M+H).
Example 162
[3,7-Bis-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diaze-
pin-4-yl]-phenyl-acetic acid methyl ester
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 7.8 7.9 (s, 1H), 7.4
7.7 (m, 11H), 7.1 7.2 (m, 1H), 6.8 7.0 (m, 4H), 6.7 (m, 1H), 5.3
(s, 0.18H), 5.25 (s, 0.82H), 3.8 (s, 3H). Mass spectrum (LCMS, ESI
pos) Calcd. for C.sub.30H.sub.22Cl.sub.2N.sub.2O.sub.4: 544.1;
Found: 545.0 (M+H).
Example 163
[3,7-Bis-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diaze-
pin-4-yl]-phenyl-acetic acid
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 7.8 7.9 (m, 1H), 7.6
7.7 (m, 1H), 7.4 7.5 (m, 4H), 7.2 7.4 (m, 6H), 7.0 7.1 (m, 1H), 6.7
6.9 (m, 4H), 5.7 (s, 0.5H), 5.45 (s, 0.5H). Mass spectrum (LCMS,
ESI pos) Calcd. for C.sub.29H.sub.20Cl.sub.2N.sub.2O.sub.4: 530.1;
Found: 531.0 (M+H).
Example 164
[7-(3-Amino-phenyl)-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo-
[e][1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 7.8 7.9 (m, 1H), 7.6
7.7 (s, 1H), 7.2 7.5 (m, 5H), 7.0 7.1 (m, 4H), 6.5 6.9 (m, 6H), 5.7
(s, 0.4H), 5.5 (br s, 0.6H). Mass spectrum (LCMS, ESI pos) Calcd.
for C.sub.29H.sub.22ClN.sub.3O.sub.4: 511.1; Found: 512.1
(M+H).
Example 165
[3-(4-Chloro-phenyl)-7-(3-isopropyl-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-b-
enzo[e][1,4]diazepin-4-yl]-phenyl-acetic acid
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 7.8 7.9 (m, 1H), 7.6
7.7 (m, 1H), 7.4 7.5 (m, 3H), 7.2 7.4 (m, 6H), 7.0 7.1 (m, 1H), 6.6
6.9 (m, 5H), 5.7 (s, 0.3H), 5.5 (s, 0.7H), 2.9 3.0 (m, 1H), 1.2 1.3
(m, 6H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.32H.sub.27ClN.sub.2O.sub.4: 538.2; Found: 539.1 (M+H).
Example 166
(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-iodo-5-oxo-2-thioxo-1,2,3,5-tetra-
hydro-benzo[e][1,4]diaze pin-4-yl]-acetic acid
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 12.3 12.5 (br s, 1H),
7.7 7.8 (m, 1H), 7.5 7.6 (m, 2H), 7.2 7.4 (m, 6H), 7.1 7.2 (m, 2H),
6.6 6.8 (m, 1H), 6.4 (s, 0.7H), 6.2 (s, 0.7H), 5.7 (m, 0.6H). Mass
spectrum (LCMS, ESI pos) Calcd. for
C.sub.23H.sub.15Cl.sub.2IN.sub.2O.sub.3S : 595.9; Found: 596.9
(M+H).
Example 167
(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-2,5-dioxo-7-vinyl-1,2,3,5-tetrahydr-
o-benzo[e][1,4]diazepin-4-yl]-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): 10.67 (s, 0.6H), 10.52 (s,
0.4H), 7.54 7.36 (m, 6H), 7.19 7.05 (m, 3H), 6.95 (m, 1H), 6.82 (d,
J=8.4 Hz, 0.6H), 6.7 (d, J=8.4 Hz, 0.4H), 6.64 6.55 (m, 1H), 6.32
(br s, 0.6H), 6.25 (br s, 0.4H), 5.73 (brs, 0.4H), 5.70 5.66 (m,
1H), 5.26 (s, 0.6H), 5.19 5.16 (m, 1H). Mass spectrum (LCMS, ESI
pos) Calcd. for C.sub.25H.sub.18N.sub.2O.sub.4Cl.sub.2: 480.06;
Found: 481.07(M+H).
Example 168
(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-cyano-2,5-dioxo-1,2,3,5-tetrahydr-
o-benzo[e][1,4]diazepin-4-yl]-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): 11.13 (s, 0.7H), 10.97 (s,
0.3H), 7.88 (m, 1H), 7.68 (m, 1H), 7.50 7.41 (m, 4H), 7.17 (m, 3H),
7.01 (m, 2H), 6.28 (br s, 0.3H), 6.27 (br s, 0.7H), 5.70 (brs,
0.3H), 5.25 (s, 0.7H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.24H.sub.15N.sub.3O.sub.4Cl.sub.2: 479.04; Found:
479.9(M+H).
Example 169
[3-(1-Chloro-cuban-4-yl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]-
diazepin-4-yl]-(4-chloro-phenyl)-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): 10.64 (s, 1H), 8.03 (d, J=2.2
Hz, 1H), 7.86 (dd, J=8.4 Hz and J=2.2 Hz, 1H), 7.47 (d, J=8.7 Hz,
2H), 7.37 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.7 Hz, 1H), 4.62 (s, 1H),
4.16 (s, 1H), 3.80 3.73 (m, 3H), 3.70 3.64 (m, 3H). Mass spectrum
(LCMS, ESI pos.): Calcd. for
C.sub.25H.sub.17Cl.sub.2IN.sub.2O.sub.4: 605.96; found: 606.99
(M+H).
Example 170
3-(4-Chloro-phenyl)-4-[1-(4-chloro-phenyl)-2-hydroxy-ethyl]-7-iodo-1,3,4,5-
-tetrahydro-benzo[e][1,4]diazepin-2-one
.sup.1H NMR (400 MHz, CDCl.sub.3): 7.50 (br s, 1H), 7.45 (dd, J=8.3
Hz and J=2.0 Hz, 1H), 7.33 (d, J=8.4 Hz, 2H), 7.29 (d, J=8.8 Hz,
2H), 7.26 (d, J=8.8 Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 7.12 (d, J=1.9
Hz, 1H), 6.49 (d, J=8.3 Hz, 1H), 5.14 (s, 1H), 4.08 4.00 (m, 1H),
3.95 3.85 (m, 2H), 3.89 (d, J=14.9 Hz, 1H), 3.58 (d, J=14.8 Hz,
1H), 2.02 1.99 (m, 1H). Mass spectrum (LCMS, ESI pos.): Calcd. for
C.sub.23H.sub.19Cl.sub.2IN.sub.2O.sub.2: 551.99; found: 552.90
(M+H).
Example 171
3-(4-Chloro-phenyl)-4-[1-(4-chloro-phenyl)-2-hydroxy-ethyl]-7-iodo-1,2,3,4-
-tetrahydro-benzo[e][1,4]diazepin-5-one
.sup.1H NMR (400 MHz, CDCl.sub.3): 8.52 (d, J=2.1 Hz, 1H), 7.36
(dd, J=8.6 Hz and J=2.2 Hz, 1H), 7.20 7.14 (m, 4H), 7.08 (d, J=8.5
Hz, 2H), 6.81 (d, J=8.4 Hz, 2H), 6.18 (d, J=8.6 Hz, 1H), 5.48 5.45
(m, 1H), 4.73 (d, J=6.0 Hz, 1H), 4.47 4.40 (m, 1H), 4.33 4.24 (m,
1H), 4.22 4.15 (m, 1H), 3.83 3.75 (m, 1H), 3.71 3.64 (m, 1H), 3.14
3.08 (m, 1H). Mass spectrum (LCMS, ESI pos.): Calcd. for
C.sub.23H.sub.19Cl.sub.2IN.sub.2O.sub.2: 551.99; found: 552.84
(M+H).
Example 172
3-(4-Chlorophenyl)-4-(2-hydroxy-1-phenyl-ethyl)-7-iodo-3,4-dihydro-1H-benz-
o[e][1,4]diazepine-2,5-dione
.sup.1H NMR (400 MHz, DMSO-d.sub.6): 10.82 (br s, 1H), 7.80 (d,
J=2.1 Hz, 1H), 7.55 (dd, J=8.5 Hz and J=2.1 Hz, 1H), 7.51 (d, J=7.4
Hz, 2H), 7.40 7.26 (m, 3H), 7.03 (d, J=8.6 Hz, 2H), 6.64 6.58 (m,
3H), 6.13 6.05 (m, 1H), 5.17 (s, 1H), 5.05 (t, J=5.0 Hz, 1H), 4.11
3.97 (m, 2H). Mass spectrum (LCMS, ESI pos.): Calcd. for
C.sub.23H.sub.18ClIN.sub.2O.sub.3: 532.01; found: 532.95 (M+H).
Example 173
3-(4-Chloro-phenyl)-4-(3-hydroxy-1-phenyl-propyl)-7-iodo-3,4-dihydro-1H-be-
nzo[e][1,4]diazepine-2,5-dione
.sup.1H NMR (400 MHz, DMSO-d.sub.6): 10.94 (s, 1H), 7.80 (d, J=2.1
Hz, 1H), 7.59 (d, J=7.3, 2H), 7.54 (dd, J=8.5 Hz and J=2.1 Hz, 1H),
7.37 (t, J=7.4 Hz, 2H), 7.30 (t, J=7.3 Hz, 1H), 6.99 (d, J=8.6 Hz,
2H), 6.64 (d, J=8.5 Hz, 1H), 6.45 (d, J=8.7 Hz, 2H), 6.33 (t, J=7.7
Hz, 1H), 5.25 (s, 1H), 4.61 (t, J=4.9 Hz, 1H), 3.48 3.39 (m, 2H),
2.28 2.20 (m, 2H). Mass spectrum (LCMS, ESI pos.): Calcd. for
C.sub.24H.sub.20ClIN.sub.2O.sub.3: 546.02; found: 546.91 (M+H).
Example 174
2-(4-Chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrah-
ydro-benzo[e][1,4]diazepin-4-yl]-N-(2-hydroxy-ethyl)-acetamide
.sup.1H NMR (400 MHz, DMSO-d.sub.6): 10.73 (s, 1H), 8.25 (t, J=5.6
Hz, 1H), 7.78 (d, J=2.1 Hz, 1H), 7.56 (dd, J=8.5 Hz and J=2.1 Hz,
1H), 7.50 7.43 (m, 4H), 7.13 (d, J=8.6 Hz, 2H), 6.91 (d, J=7.8 Hz,
2H), 6.64 (d, J=8.5 Hz, 1H), 6.48 (s, 1H), 5.00 (s, 1H), 4.65 (t,
J=5.3 Hz, 1H), 3.42 3.37 (m, 2H), 3.29 3.05 (m, 2H). Mass spectrum
(LCMS, ESI pos.): Calcd. for
C.sub.25H.sub.20Cl.sub.2IN.sub.3O.sub.4: 622.99; found: 623.75
(M+H).
Example 175
3-(4-Chloro-phenyl)-3-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrah-
ydro-benzo[e][1,4]diazepin-4-yl]-propionic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.90 (s, 1H), 7.81
(d, J=2.4 Hz, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.56 (dd, J=8.0 Hz, 2.0
Hz, 1H), 7.41 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.4 Hz, 2H), 6.61 (d,
J=8.4 Hz, 1H), 6.54 (d, J=8.8 Hz, 2H), 6.42 (t, J=8.0 Hz, 1H), 5.31
(s, 1H), 3.15 (d, J=7.2 Hz, 1H). Mass spectrum (LCMS, ESI pos)
Calcd. for C.sub.24H.sub.17Cl.sub.2IN.sub.2O.sub.4: 593.96; Found
594.90 (M+H).
Example 176
[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diaz-
epin-4-yl]-(6-chloro-pyridin-3-yl)-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.64 (s, 0.7H), 10.61
(s, 0.3H), 8.46 (d, J=2.4 Hz, 0.7H), 8.34 (d, J=2.4 Hz, 0.3H), 7.93
7.90 (m, 0.7H), 7.81 7.80 (m, 0.3H), 7.78 (d, J=2 Hz, 0.7H), 7.71
(d, J=2.4 Hz, 0.3H), 7.54 7.51 (m, 1H), 7.46 7.41 (m, 1H), 7.19
7.13 (m, 2.6H), 7.04 7.02 (m, 1.4H), 6.62 (d, J=8.8 Hz, 0.7H), 6.56
(d, J=8.8 Hz, 0.3H), 6.25 (s, 0.3H), 6.04 (s, 0.7H), 5.81 (s,
0.3H), 5.40 (s, 0.7H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.22H.sub.14Cl.sub.2IN.sub.3O.sub.4: 580.94; Found 581.93
(M+H).
Example 177
2-(4-Chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrah-
ydro-benzo[e][1,4]diazepin-4-yl]-N-hydroxy-acetamide
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.83 (s, 1H), 7.73
(d, J=2.0 Hz, 1H), 7.76 (dd, J=8.0 Hz, 2.0 Hz, 1H), 7.52 7.45 (m,
3H), 7.20 (d, J=8.8 Hz, 2H), 7.07 (d, J=8.8 Hz, 2H), 6.64 (d, J=8.4
Hz, 1H), 6.20 (s, 1H), 5.24 (s, 1H). Mass spectrum (LCMS, ESI neg)
Calcd. for C.sub.23H.sub.16Cl.sub.2IN.sub.3O.sub.4: 594.96; Found
578.9.
Example 178
[7-Bromo-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]dia-
zepin-4-yl]-(4-chloro-phenyl)-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.68 (s, 1H), 7.60
(d, J=2.4 Hz, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.44 7.39 (m, 3H), 7.10
(d, J=8.8 Hz, 2H), 6.93 6.85 (m, 2H), 6.78 (d, J=8.8 Hz, 1H), 6.24
(s, 1H), 5.22 (s, 1H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.23H.sub.15BrcCl.sub.2N.sub.2O.sub.4: 531.96; Found 532.90
(M+H).
Example 179
[8-Chloro-3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e]-
[1,4]diazepin-4-yl]-(4-chloro-phenyl)-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.78 (s, 1H), 7.98
(s, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 7.10 (d,
J=8.4 Hz, 2H), 7.04 (s, 1H), 6.82 (d, J=8.4 Hz, 2H), 6.26 (s, 1H),
5.21 (s, 1H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.23H.sub.14Cl.sub.3IN.sub.2O.sub.4: 613.91; Found 614.8
(M+H).
Example 180
2-{2-(4-Chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tet-
rahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-3-methyl-butyric
acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.80 10.69 (m, 1H),
8.58 8.47 (m, 1H), 7.62 7.29 (m, 3H), 7.25 6.83 (m, 5H), 6.80 6.50
(m, 2H), 5.04 (s, 0.5H), 4.86 (s, 0.5H), 4.27 4.08 (m, 1H), 2.07
1.97 (m, 1H), 0.92 0.81 (m, 6H). Mass spectrum (LCMS, ESI pos)
Calcd. for C.sub.28H.sub.24Cl.sub.2IN.sub.3O.sub.5: 679.01; Found
679.66 (M+H).
Example 181
3-(4-Chloro-phenyl)-3-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrah-
ydro-benzo[e][1,4]diazepin-4-yl]-propionic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.88 (s, 1H), 7.80
(d, J=2.4 Hz, 1H), 7.59 7.50 (m, 3H), 7.35 (d, J=8.0 Hz, 2H), 7.05
(d, J=8.0 Hz, 2H), 6.64 6.58 (m, 3H), 6.42 6.36 (m, 1H), 5.10 (s,
1H), 2.95 2.86 (m, 1H), 2.4 2.34 (m, 1H).
Example 182
5-{2-(4-Chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tet-
rahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-pentanoic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 12.00 (s, 1H), 10.72
(s, 1H), 8.25 (t, J=5.6 Hz, 1H), 7.77 (d, J=2.0 Hz, 1H), 7.60 7.52
(m, 1H), 7.50 7.41 (m, 4H), 7.13 (dd, J=8.0 Hz, 2.0 Hz, 2H), 6.90
(dd, J=8.0 Hz, 1.2 Hz, 2H), 6.64 (d, J=8.4 Hz, 1H), 6.42 (s, 1H),
4.98 (s, 1H), 3.22 2.98 (m, 2H), 2.23 2.17 (m, 2H), 1.52 1.34 (m,
4H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.28H.sub.24Cl.sub.2IN.sub.3O.sub.5: 679.01; Found 679.86
(M+H).
Example 183
3-{2-(4-Chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tet-
rahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-propionic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.73 (s, 1H), 8.37
8.28 (m, 1H), 7.77 (d, J=2.0 Hz, 1H), 7.58 7.53 (m, 1H), 7.46 7.42
(m, 4H), 7.13 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.4 Hz, 2H), 6.64 (d,
J=8.4 Hz, 1H), 6.43 (s, 1H), 4.97 (s, 1H), 3.17 (d, J=5.6 Hz, 2H),
2.42 2.38 (m, 2H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.26H.sub.20Cl.sub.2IN.sub.3O.sub.5: 650.98; Found 651.68
(M+H).
Example 184
(4-Chloro-phenyl)-[7-iodo-2,5-dioxo-3-(4-trifluoromethylsulfanyl-phenyl)-1-
,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid
Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.24H.sub.15ClF.sub.3IN.sub.2O.sub.4S: 645.94; Found 646.96
(M+H).
Example 185
(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-2,5-dioxo-7-(1H-pyrrol-3-yl)-1,2,3,-
5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.94 (s, 1H), 10.60
(s, 1H), 7.66 7.35 (m, 6H), 7.22 7.03 (m, 5H), 6.79 6.72 (m, 2H),
6.34 6.28 (m, 1H), 6.21 (s, 1H), 5.25 (s, 1H).
Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.27H.sub.19Cl.sub.2N.sub.3O.sub.4: 519.08; Found 520.00
(M+H).
Example 186
3-[4-[Carboxy-(4-chloro-phenyl)-methyl]-3-(4-chloro-phenyl)-7-iodo-2,5-dio-
xo-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-yl]-propionic
acid
.sup.1H NMR (400 MHz, CD.sub.3OD-d.sub.6): .delta. 8.06 7.89 (m,
1.2H), 7.83 (d, J=8.4 Hz, 0.6H), 7.74 7.68 (m, 0.6H), 7.56 (d,
J=8.0 Hz, 1H), 7.47 7.24 (m, 3H), 7.08 6.93 (m, 2H), 6.82 6.57 (m,
2H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.26H.sub.19Cl.sub.2IN.sub.2O.sub.6: 651.97; Found 652.90
(M+H).
Example 187
6-{2-(4-Chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tet-
rahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-hexanoic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 11.98 (s, 1H), 10.72
(s, 1H), 8.29 8.15 (m, 1H), 7.77 (d, J=2.0 Hz, 1H), 7.59 7.53 (m,
1H), 7.51 7.42 (m, 4H), 7.13 (d, J=8.8 Hz, 2H), 6.91 (d, J=7.6 Hz,
2H), 6.64 (d, J=8.4 Hz, 1H), 6.41 (s, 1H), 4.98 (s, 1H), 3.20 2.95
(m, 2H), 2.16 (t, J=7.6 Hz, 2H), 1.53 1.31 (m, 4H), 1.26 1.15 (m,
2H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.29H.sub.26Cl.sub.2IN.sub.3O.sub.5: 693.03; Found 693.82
(M+H).
Example 188
[1-(2-tert-Butoxycarbonylamino-ethyl)-3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-
-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4-chloro-phenyl)-acetic
acid
.sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 7.94 (d, J=2.0 Hz, 1H),
7.53 (d, J=8.4 Hz, 2H), 7.47 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.29 (d,
J=8.0 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 6.73 (dd, J=8.0 Hz, 1.6 Hz,
2H), 6.61 (d, J=8.4 Hz, 1H), 6.50 (s, 1H), 5.27 (s, 1H), 3.55 3.49
(m, 2H), 3.50 3.45 (m, 1H), 3.15 3.10 (m, 1H). Mass spectrum (LCMS,
ESI pos) Calcd. for C.sub.30H.sub.28Cl.sub.2IN.sub.3O.sub.6:
723.04; Found 723.70 (M+H).
Example 189
(4-Chloro-phenyl)-{7-iodo-2,5-dioxo-3-[5-(3-trifluoromethyl-phenyl)-furan--
2-yl]-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl}-acetic
acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.03 (s, 1H), 7.68
7.56 (m, 4H), 7.57 7.44 (m, 4H), 7.40 7.33 (m, 2H), 6.79 (d, J=8.4
Hz, 1H), 6.73 (s, 1H), 6.48 (d, J=3.2 Hz, 1H), 5.61 5.57 (m, 1H),
5.49 (s, 1H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.28H.sub.17ClF.sub.3IN.sub.2O.sub.5: 679.98; Found 680.77
(M+H).
Example 190
(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1-(2-pyridin-2-yl--
ethyl)-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetic
acid
Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.30H.sub.22Cl.sub.2IN.sub.3O.sub.4: 685.00; Found 686.18
(M+H).
Example 191
(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-iodo-1-methylcarbamoylmethyl-2,5--
dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetic
acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.84 7.81 (m, 1H),
7.52 7.46 (m, 3H), 7.33 7.27 (m, 2H), 6.91 (d, J=8.4 Hz, 2H), 6.80
(d, J=8.4 Hz, 1H), 6.69 (d, J=8.8 Hz, 2H), 6.57 (s, 1H), 5.33 (s,
1H), 4.50 (m, 1H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.26H.sub.20Cl.sub.2IN.sub.3O.sub.5: 650.98; Found 651.94
(M+H).
Example 192
(4-Chloro-phenyl)-[3-(4-difluoromethoxy-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-t-
etrahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid
.sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 7.93 (d, J=2.0 Hz,
0.6H), 7.89 (d, J=2.0 Hz, 0.4H), 7.59 (d, J=8.0 Hz, 1H), 7.54 7.48
(m, 1H), 7.45 (d, J=8.4 Hz, 0.6H), 7.37 7.30 (m, 2.4H), 7.13 7.05
(m, 0.4H), 6.85 (d, J=8.4 Hz, 0.6H), 6.82 6.70 (m, 2.3H), 6.68 6.65
(m, 0.6H), 6.64 6.58 (m, 1H), 5.70 (s, 0.3H), 5.37 (s, 1H). Mass
spectrum (LCMS, ESI pos) Calcd. for
C.sub.24H.sub.16ClF.sub.2IN.sub.2O.sub.5: 611.98; Found 612.80
(M+H).
Example 193
[1-(2-tert-Butoxycarbonylamino-ethyl)-3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-
-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4-chloro-phenyl)-acetic
acid
.sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 7.84 (d, J=2.0 Hz, 1H),
7.57 7.45 (m, 3H), 7.37 (d, J=8.4 Hz, 2H), 7.12 (d, J=8.4 Hz, 2H),
7.00 (d, J=8.8 Hz, 2H), 6.82 (d. J=8.8 Hz, 1H), 6.56 (s, 1H), 5.76
(s, 1H), 4.11 3.98 (m, 1H), 3.78 3.65 (m, 1H), 3.16 3.08 (m, 2H),
1.39 (s, 9H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.30H.sub.28Cl.sub.2IN.sub.3O.sub.6: 723.04; Found 745.90
(M+Na)
Example 194
(3-Benzofuran-2-yl-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazep-
in-4-yl)-(4-chloro-phenyl)-acetic acid
.sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 8.01 (d, J=1.6 Hz, 1H),
7.64 (d, J=8.8 Hz, 2H), 7.58 7.51 (m, 1H), 7.49 7.44 (m, 1H), 7.40
7.32 (m, 2H), 7.26 6.95 (m, 4H), 6.83 6.72 (m, 1H), 5.92 (s, 0.7H),
5.80 (s, 0.3H), 5.64 (s 0.3H), 5.56 (s, 0.7H). Mass spectrum (LCMS,
ESI pos) Calcd. for C.sub.25H.sub.16ClIN.sub.2O.sub.5: 585.98;
Found 586.93 (M+H).
Example 195
(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-iodo-1-methyl-2,5-dioxo-1,2,3,5-t-
etrahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid
.sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 7.84 (d, J=2.0 Hz, 1H),
7.62 7.54 (m, 3H), 7.34 (d, J=8.4 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H),
6.82 (d, J=8.8 Hz, 1H), 6.68 (dd, J=8.8 Hz, 1.2 Hz, 2H), 6.53 (s,
1H), 5.38 (s, 1H), 3.44 (s, 3H). Mass spectrum (LCMS, ESI pos)
Calcd. for C.sub.24H.sub.17Cl.sub.2IN.sub.2O.sub.4: 593.96; Found
594.95 (M+H).
Example 196
(4-Chloro-phenyl)-[3-(4-cyano-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro--
benzo[e][1,4]diazepin-4-yl]-acetic acid
.sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 7.91 (d, J=2.0 Hz, 1H),
7.59 (d, J=8.4 Hz, 1H), 7.55 7.42 (m, 3H), 7.39 7.27 (m, 3H), 6.98
(d, J=8.4 Hz, 1H), 6.65 (d, J=7.6 Hz, 1H), 6.59 (d, J=8.4 Hz,
0.5H), 6.51 (d, J=8.8 Hz, 0.5H), 5.77 (s, 0.5H), 5.44 (s,
0.5H).
Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.24H.sub.15ClIN.sub.3O.sub.4: 570.98; Found 571.80 (M+H).
Example 197
[1-Carboxymethyl-3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-b-
enzo[e][1,4]diazepin-4-yl]-(4-chloro-phenyl)-acetic acid methyl
ester
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.73 6.75 (m, 11H),
6.24 (s, 1H), 5.42 (s, 1H), 4.53 4.25 (m, 1H), 4.16 3.86 (m, 1H),
3.78 (s, 3H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.26H.sub.19Cl.sub.2IN.sub.2O.sub.6: 651.97; Found 652.87
(M+H).
Example 198
(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-(2-hydroxy-ethyl)-2,5-dioxo-1,2,3-
,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.46 (s, 1H), 7.62
7.26 (m, 4H), 7.08 6.96 (m, 3H), 6.82 6.66 (m, 3H), 6.30 (s, 1H),
5.29 (s, 1H), 4.59 (s, 1H), 3.45 3.39 (m, 2H), 2.55 (t, J=8.8 Hz,
2H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.25H.sub.20Cl.sub.2N.sub.2O.sub.5: 498.07; Found 498.95
(M+H).
Example 199
(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-1-(2(R),3-dihydroxy-propyl)-7-iodo--
2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetic
acid
Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.26H.sub.21Cl.sub.2IN.sub.2O.sub.6: 653.98; Found 654.81
(M+H).
Example 200
(4-Chloro-phenyl)-[3-(6-chloro-pyridin-3-yl)-7-iodo-2,5-dioxo-1,2,3,5-tetr-
ahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid
.sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 7.63 7.57 (m, 2H), 7.30
(d, J=8.4 Hz, 2H), 7.00 6.89 (m, 3H), 6.78 6.65 (m, 4H), 5.41 (s,
1H).
Example 201
(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-hydroxymethyl-2,5-dioxo-1,2,3,5-t-
etrahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.52 (s, 1H), 7.57
7.42 (m, 2H), 7.41 7.23 (m, 3H), 7.22 6.96 (m, 4H), 6.87 6.67 (m,
3H), 6.33 (s, 1H), 5.18 (s, 1H), 4.38 4.27 (m, 2H).
Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.24H.sub.18Cl.sub.2N.sub.2O.sub.5: 484.06; Found 485.00
(M+H).
Example 202
(4-Chloro-phenyl)-{7-iodo-2,5-dioxo-3-[4-(1,1,2,2-tetrafluoro-ethoxy)-phen-
yl]-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl}-acetic acid
.sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 7.96 (d, J=2.0 Hz,
0.4H), 7.80 (d, J=2.0 Hz, 0.6H), 7.54 7.47 (m, 1H), 7.39 (d, J=8.4
Hz, 2H), 7.29 7.12 (m, 5H), 7.06 (d, J=8.4 Hz, 2H), 6.85 (t, J=8.0
Hz, 1.8H), 6.62 (s, 0.7H), 5.96 (s, 0.6H), 5.79 (s, 0.4H), 5.36
5.28 (m, 1H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.25H.sub.16ClF.sub.4IN.sub.2O.sub.5: 661.97; Found 662.90
(M+H).
Example 203
(4-Chloro-phenyl)-[7-iodo-3-(4-methylsulfanyl-phenyl)-2,5-dioxo-1,2,3,5-te-
trahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid
.sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 7.92 (s, 0.7H), 7.88 (s,
0.3H), 7.58 (d, J=8.0 Hz, 1H), 7.56 7.41 (m, 1.7H), 7.38=7.29 (m,
1.7H), 7.20 (d, J=8.0 Hz, 0.7H), 7.08 (d, J=8.0 .sub.Hz, 0.3H),
7.02 6.89 (m, 1H), 6.86 6.69 (m, 1H), 6.70 6.63 (m, 1.3H), 6.60 (d,
J=8.8 Hz, 0.7H), 6.51 (d, J=8.8 Hz, 0.3H), 5.70 (s, 0.3H), 5.35 (s,
0.7H), 2.34 (s, 1H), 2.29 (s, 2H). Mass spectrum (LCMS, ESI pos)
Calcd. for C.sub.24H.sub.18ClIN.sub.2O.sub.4S: 591.97; Found 592.90
(M+H).
Example 204
(4-Chloro-phenyl)-[7-iodo-2,5-dioxo-3-(4-pyrrolidin-1-yl-phenyl)-1,2,3,5-t-
etrahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid
.sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 8.18 8.08 (m, 1H), 7.98
7.85 (m, 1H), 7.59 (d, J=1.2 Hz, 1H), 7.52 7.42 (m, 2H), 7.39 7.28
(m, 3H), 7.06 (d, J=8.0 Hz, 1H), 6.74 6.45 (m, 1H), 6.29 (d, J=8.4
Hz, 1H), 6.09 (dd, J=8.0 Hz, 1.2 Hz, 1H), 5.66 (s, 0.5H), 5.36 (s,
0.5H), 3.17 3.02 (m, 4H), 1.99 1.87 (m, 4H). Mass spectrum (LCMS,
ESI pos) Calcd. for C.sub.27H.sub.23ClIN.sub.3O.sub.4: 615.04;
Found 616.07 (M+H).
Example 205
2-(4-Chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrah-
ydro-benzo[e][1,4]diazepin-4-yl]-N,N-bis-(2-hydroxy-ethyl)-acetamide
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.65 (s, 0.5H), 8.20
(s, 0.5H), 8.00 (d, J=1,6 Hz, 0.5H), 7.94 (d, J=2.0 Hz, 0.5H), 7.52
7.42 (m, 2.5H), 7.37 (d, J=8.8 Hz, 1H), 7.24 (dd, J=5.6 Hz, 1h),
7.10 6.99 (m, 2H), 6.95 (s, 1H), 6.85 (d, J=8.0 Hz, 0.5H), 6.46
6.35 (m, 1H), 5.32 (s, 0.5H), 5.12 (s, 0.5H), 4.04 3.06 (m, 8H).
Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.27H.sub.24Cl.sub.2IN.sub.3O.sub.5: 667.01; Found 667.85
(M+H).
Example 206
(4-Chloro-phenyl)-{7-iodo-2,5-dioxo-3-[4-(1,1,2,2-tetrafluoro-ethoxy)-phen-
yl]-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl}-acetic acid
.sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 7.83 7.74 (m, 0.7H),
7.60 (d, J=8.4 Hz, 0.6H), 7.52 7.45 (m, 0.7H), 7.42 7.30 (m, 2H),
7.27 (d, J=8.4 Hz, 1H), 7.17 (d, J=7.6 Hz, 2H), 7.09 6.97 (m, 3H),
6.89 6.78 (m, 2H), 6.63 (s, 0.6H), 6.46 (s, 0.4H), 5.97 (s, 0.5H),
5.60 5.51 (m, 0.6H), 5.37 5.27 (m, 0.7H), 4.66 4.58 (m, 0.5H). Mass
spectrum (LCMS, ESI pos) Calcd. for
C.sub.25H.sub.16ClF4IN.sub.2O.sub.5: 661.97; Found 662.89
(M+H).
Example 207
[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diaz-
epin-4-yl]-(6-methyl-pyridin-3-yl)-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.76 (s, 1H), 8.53
(d, J=2.0 Hz, 1H), 7.78 7.72 (m, 2H), 7.60 7.53 (m, 1H), 7.26 7.16
(m, 3H), 7.10 7.03 (m, 2H), 6.65 (d, J=8.8 Hz, 1H), 6.16 (s, 1H),
5.33 (s, 1H), 2.42 (s, 3H). Mass spectrum (LCMS, ESI pos) Calcd.
for C.sub.23H.sub.17ClIN.sub.3O.sub.4: 561.00; Found 562.01
(M+H).
Example 208
3-{2-(4-Chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tet-
rahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-propionic acid
methyl ester
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.74 (s, 1H), 8.35
(t, J=6.0 Hz, 1H), 7.77 (d, J=2.0 Hz, 1H), 7.61 7.51 (m, 1H), 7.45
(s, 2H), 7.13 (d, J=8.4 Hz, 2H), 6.91 (d, J=7.8 Hz 2H), 6.64 (d,
J=7.8 Hz, 1H), 6.42 (s, 1H), 4.98 (s, 1H), 3.56 (s, 3H), 3.48 3.36
(m, 1H), 3.31 3.21 (m, 1H), 2.48 2.40 (m, 2H). Mass spectrum (LCMS,
ESI pos) Calcd. for C.sub.27H.sub.22Cl.sub.2IN.sub.3O.sub.5:
665.00; Found 665.70 (M+H).
Example 209
[7-Amino-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]dia-
zepin-4-yl]-(4-chloro-phenyl)-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 12.00 (s, 1H), 10.20
(s, 1H), 7.53 7.35 (m, 3H), 7.27 (d, J=8.4 Hz, 0.4H), 7.19 6.96 (m,
2.8H), 6.88 6.66 (m, 1.2H0, 6.54 6.39 (m, 1.4H), 6.10 (s, 0.7H),
5.18 (s, 0.8H), 5.00 (s, 1.0H), 4.42 (s, 0.4H). Mass spectrum
(LCMS, ESI pos) Calcd. for C.sub.23H.sub.17Cl.sub.2N.sub.3O.sub.4:
469.06; Found 470.00 (M+H).
Example 210
2-(4-Chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrah-
ydro-benzo[e][1,4]diazepin-4-yl]-N-(2-hydroxyguanidino-ethyl)-acetamide
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.95 (s, 1H), 10.75
(s, 1H), 8.41 (m, 1H), 7.77 (d, J=2.0 Hz, 1H), 7.57 (dd, J=8.4 Hz,
2.4 Hz, 1H), 7.53 7.44 (m, 3H), 7.14 (d, J=8.8 Hz, 2H), 6.93 (d,
J=8.4 Hz, 2H), 6.65 (d, J=8.8 Hz 1H), 6.43 (s, 1H), 4.99 (s, 1H),
3.80 (t, J=5.6 Hz, 2H), 3.46 3.36 (m, 4H). Mass spectrum (LCMS, ESI
pos) Calcd. for C.sub.26H.sub.23Cl.sub.2IN.sub.6O.sub.4: 680.02;
Found 681.00 (M+H).
Example 211
(4-Chloro-phenyl)-[3-(5-chloro-thiophen-2-yl)-7-iodo-2,5-dioxo-1,2,3,5-tet-
rahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid
.sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 7.99 7.89 (m, 1H), 7.67
7.51 (m, 2H), 7.44 7.32 (m, 2H), 7.27 6.99 (m, 1H), 6.90 6.82 (m,
0.5H), 6.73 (d, J=8.4 Hz, 0.5H), 6.67 6.41 (m, 2H), 6.23 6.18 (m,
0.5H), 5.44 5.38 (m, 0.5H). Mass spectrum (LCMS, ESI pos) Calcd.
for C.sub.21H.sub.13Cl.sub.2IN.sub.2O.sub.4S: 585.90; Found 586.72
(M+H).
Example 212
(4-Chloro-phenyl)-[7-iodo-3-(4-isopropenyl-cyclohex-1-enyl)-2,5-dioxo-1,2,-
3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.31 (s, 0.8H), 10.15
(s, 0.2H), 7.93 7.78 (m, 1H), 7.72 7.64 (m, 1H), 7.44 7.24 (m, 4H),
6.83 6.73 (m, 1H), 6.20 6.11 (m, 1H), 5.05 4.93 (m, 1H), 4.57 4.44
(m, 2H), 4.35 4.24 (m, 1H), 1.71 1.21 (m, 10H). Mass spectrum
(LCMS, ESI pos) Calcd. for C.sub.26H.sub.24ClIN.sub.2O.sub.4:
590.05; Found 591.00 (M+H).
Example 213
(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-1-(2(S),3-dihydroxy-propyl)-7-iodo--
2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetic
acid
.sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 7.87 7.80 (m, 1H), 7.61
7.45 (m, 3H), 7.38 7.28 (m, 2H), 7.19 6.91 (m, 4H), 6.80 6.71 (m,
1H), 6.62 (s, 0.3H), 5.89 (s, 0.6H), 4.30 3.38 (m, 5H). Mass
spectrum (LCMS, ESI pos) Calcd. for
C.sub.26H.sub.21Cl.sub.2IN.sub.2O.sub.6: 653.98; Found 637.20.
Example 214
5-[4-[Carboxy-(4-chloro-phenyl)-methyl]-3-(4-chloro-phenyl)-7-iodo-2,5-dio-
xo-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-yl]-pentanoic
acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.97 7.91 (m, 1H),
7.66 (d, J=8.4 Hz, 1H), 7.46 7.41 (m, 4H), 7.03 (d, J=8.4 Hz, 2H),
6.73 (d, J=8.4 Hz, 1H), 6.67 (s, 1H), 6.64 (d, J=8.4 Hz, 2H), 5.48
(s, 1H), 4.57 4.45 (m, 1H), 3.75 3.65 (m, 1H), 2.49 2.39 (m, 2H),
1.75 1.55 (m, 4H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.28H.sub.23Cl.sub.2IN.sub.2O.sub.6: 680.00; Found 680.85
(M+H).
Example 215
5-{3-(4-Chloro-phenyl)-4-[1-(4-chloro-phenyl)-2-hydroxy-ethyl]-7-iodo-2,5--
dioxo-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-yl}-pentanoic
acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.85 (d, J=2 Hz, 1H),
7.61 7.52 (m, 3H), 7.38 (d, J=8.4 Hz, 2H), 6.97 6.87 (m, 3H), 6.58
(dd, J=2.0 Hz, 8.0 Hz, 2H), 6.28 6.20 (m, 1H), 5.39 (s, 1H), 4.36
4.24 (m, 2H), 4.20 4.12 (m, 1H), 3.83 3.72 (m, 1H), 2.23 2.11 (m,
2H), 1.84 1.65 (m, 2H), 1.64 1.52 (m, 2H). Mass spectrum (LCMS, ESI
pos) Calcd. for C.sub.28H.sub.25Cl.sub.2IN.sub.2O.sub.5: 666.02;
Found 666.97 (M+H).
Example 216
5-{3-(4-Chloro-phenyl)-4-[(4-chloro-phenyl)-diethylcarbamoyl-methyl]-7-iod-
o-2,5-dioxo-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-yl}-pentanoic
acid
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.65 (d, J=2.4 Hz,
1H), 7.62 7.55 (m, 3H), 7.53 7.48 (m, 2H), 7.12 7.06 (m, 2H), 6.94
6.87 (m, 2H), 6.60 (s, 1H), 4.89 (s, 1H), 4.24 4.14 (m, 1H), 3.74
3.63 (m, 1H), 3.57 3.47 (m, 2H), 3.17 3.08 (m, 2H), 2.23 2.13 (m,
2H), 1.85 1.73 (m, 1H), 1.67 1.58 (m, 1H), 1.49 1.40 (m, 2H), 1.10
0.98 (m, 6H). Mass spectrum (LCMS, ESI pos) Calcd. for
C.sub.32H.sub.32Cl.sub.2IN.sub.3O.sub.5: 735.08; Found 735.82
(M+H).
Example 217
Fluorescent Peptide Assay
The inhibition of MDM2 binding to p53 was measured using a p53
peptide analogue binding to MDM2 residues 17 125. The published
crystal structure of this complex (Kussie et al., Science 274:948
953 (1996)) validates this fragment as containing the p53 binding
site, and we have solved the x-ray structure of the p53 peptide
analogue MPRFMDYWEGLN, described to be a peptide inhibitor of the
MDM2 p53 interaction (Bottger et al., J. Mol. Biol. 269:744 756
(1997)). The assay uses N terminal fluorescein RFMDYWEGL peptide
(Fl 9 mer).
The mdm2 17 125 was produced as a glutathione S transferase fusion
as follows: cDNA encoding residues 17 125 were cloned into pGEX4t-3
(Pharmacia) as follows. PCR was performed using ATCC item number
384988 containing partial human mdm2 sequence as template and the
following primers: Forward: 5'-CTC TCT CGG ATC CCA GAT TCC AGC TTC
GGA ACA AGA G; Reverse: 5'-TAT ATA TCT CGA GTC AGT TCT CAC TCA CAG
ATG TAC CTG AG. The PCR product was then digested with BamHI and
XhoI (sequence recognition sites underlined in primers), gel
purified, and ligated into pGEX4t-3 which had also been digested
with BamHI and XhoI. Plasmids were transfected into E. coli X90
strain, grown to an OD of 1.0 in TB 0.2% glucose 100 .mu.g/mL
ampicillin and induced with 1 mM IPTG. Cells were harvested 5 hours
post induction, centrifuged, and resuspended in PBS 10 mL/g cell
paste. Cells were lysed in an Avestin microfluidizer, centrifuged,
and the supernatant bound to a glutathione sepharose 4B resin
(Pharmacia). The resin was washed with PBS and the MDM2 17 125
cleaved from the GST by the addition of 2 .mu.g/mL thrombin (Enzyme
Research Labs). The cleaved MDM2 was further purified on Sepharose
SP Fast Flow resin (Pharmacia), eluting with 20 mM HEPES pH 7.5 150
mM NaCl. Glutathione was added to 5 mM, and the protein stored at
-70.degree. C.
Test compound was incubated for 15 minutes with 30 nM fluorescein
peptide Fl 9 mer and 120 nM MDM2 17 125 in 50 mM HEPES pH 7.5, 150
mM NaCl, 3 mM octyl glucoside. The polarization of the fluorescein
label was thereafter measured by excitation at 485 nm and emission
at 530 nm. Polarization was expressed as a percent of a no compound
control, using buffer with Fl 9 mer but without MDM2 as
background.
Compounds of the present invention inhibited the binding of p53 to
MDM2. The potency of the compounds was measured as IC.sub.50, which
is a measure of the concentration of the test compound required to
inhibit 50% binding between MDM2 and p53. The IC.sub.50 values for
compounds of the present invention ranged from 0.1 .mu.M to >100
.mu.M. Table 1 provides representative data for compounds of the
invention.
TABLE-US-00001 TABLE 1 Inhibition of MDM2 binding to p53 Example
No. IC.sub.50 (.mu.M) 1 1.7 4 1.8 10 13 12 56 27 7.8 32 10.1 39
11.7 46 10.5 56 1.9 74 10 88 0.87 102 1.7 111 0.58 125 0.62 130
0.47 145 0.62
Example 218
Tablet Preparation
Tablets containing 25.0, 50.0, and 100.0 mg, respectively, of the
compound of Example 1 ("active compound") are prepared as
illustrated below:
TABLE-US-00002 TABLET FOR DOSES CONTAINING FROM 25 100 MG OF THE
ACTIVE COMPOUND Amount-mg Active compound 25.0 50.0 100.00
Microcrystalline cellulose 37.25 100.0 200.0 Modified food corn
starch 37.25 4.25 8.5 Magnesium stearate 0.50 0.75 1.5
All of the active compound, cellulose, and a portion of the corn
starch are mixed and granulated to 10% corn starch paste. The
resulting granulation is sieved, dried and blended with the
remainder of the corn starch and the magnesium stearate. The
resulting granulation is then compressed into tablets containing
25.0, 50.0, and 100.0 mg, respectively, of active ingredient per
tablet.
Example 219
Intravenous Solution Preparation
An intravenous dosage form of the compound of Example 1 ("active
compound") is prepared as follows:
TABLE-US-00003 Active compound 0.5 10.0 mg Sodium citrate 5 50 mg
Citric acid 1 15 mg Sodium chloride 1 8 mg Water for injection
(USP) q.s. to 1 ml
Utilizing the above quantities, the active compound is dissolved at
room temperature in a previously prepared solution of sodium
chloride, citric acid, and sodium citrate in Water for Injection
(USP, see page 1636 of United States Pharmacopeia/National
Formulary for 1995, published by United States Pharmacopeial
Convention, Inc., Rockville, Md. (1994).
Having now fully described this, invention, it will be understood
by those of ordinary skill in the art that the same can be
performed within a wide and equivalent range of conditions,
formulations and other parameters without affecting the scope of
the invention or any embodiment thereof. All patents and
publications cited herein are fully incorporated by reference
herein in their entirety.
* * * * *